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WO2025067459A2 - Thérapies pour le traitement du cancer - Google Patents

Thérapies pour le traitement du cancer Download PDF

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Publication number
WO2025067459A2
WO2025067459A2 PCT/CN2024/121852 CN2024121852W WO2025067459A2 WO 2025067459 A2 WO2025067459 A2 WO 2025067459A2 CN 2024121852 W CN2024121852 W CN 2024121852W WO 2025067459 A2 WO2025067459 A2 WO 2025067459A2
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cancer
kras
inhibitor
alkyl
optionally substituted
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WO2025067459A3 (fr
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Zhijian Chen
Jing Zhang
Tienan WANG
Wenqian WANG
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D3 Bio Wuxi Co Ltd
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D3 Bio Wuxi Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present application relates to therapies (e.g., combination therapies) for treating cancers with an ERK1/2 inhibitor and/or a KRAS G12C inhibitor.
  • Ras/Raf/MEK/ERK pathway is a classic mitogen activated protein kinase (MAPK) signaling cascade pathway, which is involved in the activation of various growth factors, cytokines, mitogens and hormone receptors and is one of the most important signal transduction pathways controlling cell growth, differentiation and survival.
  • MAPK mitogen activated protein kinase
  • KRAS is a key regulator of cytokines that shape the tumor microenvironment.
  • KRAS mutations play a role in many cancers. The incidence of KRAS mutations in human tumors is about 22%.
  • the KRAS G12C mutation accounts for about 44%of all KRAS mutations.
  • G12C is a single point mutation with a glycine-to-cysteine substitution at codon 12 of the KRAS protein that favors the active, GTP-bound conformation. This promotes constitutive activation of the signaling pathways that lead to oncogenesis.
  • KRAS G12C inhibitors have recently demonstrated clinical efficacy, the overall response rates (ORR) for both sotorasib and adagrasib (MRTX849) , two clinical stage KRAS G12C inhibitors, are within the 30-40%range. These data indicate a significant proportion of the KRAS G12C mutation population carry primary resistance to KRAS G12C inhibition.
  • Use of G12C inhibitors in combination with other pathway inhibitors has been explored to further enhance the anti-tumor effect of KRAS G12C inhibition is a highly relevant strategy to overcome primary resistance and to improve overall response rate.
  • the use of inhibitors at these upstream nodes can quickly lead to drug resistance problems due to mutations or pathway reactivation, which greatly limits their clinical applications.
  • the adaptive feedback reactivation of the RAS-RAF-MEK-ERK signaling cascade is key molecular mechanisms driving primary and acquired resistance to KRAS G12C inhibitors. Achieving deeper and more durable responses in these patients remain as major challenges.
  • the present application in one aspect provides a method of treating cancer in an individual, comprising administering to the individual an effective amount of 1) an ERK1/2 inhibitor; and 2) a KRAS G12C inhibitor.
  • the ERK1/2 inhibitor comprises an agent comprising the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1- 3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n 0 or 1
  • n 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1- 3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • the ERK1/2 inhibitor is selected from:
  • the ERK1/2 inhibitor comprises an agent comprising the following formula or a pharmaceutically acceptable salt thereof,
  • the KRAS G12C inhibitor is a small molecule.
  • the KRAS G12C inhibitor is selected from the group consisting of: sotorasib, adagrasib, JAB-21822, GDC-6036, JDQ443, D-1553, GH35, GFH925, BPI-421286, and LY3537982, RMC-6291, RMC-8839, HBI-2438, and JNJ-74699157.
  • the KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from O and N;
  • R 1 is selected from C 6-10 aryl and 5-to 10-membered heteroaryl, wherein the C 6-10 aryl and 5-to 10-membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 R a ;
  • R 2 is selected from H, C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1- 3 alkyl, wherein the C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1-3 alkyl are optionally substituted with 1, 2 or 3 R b ;
  • R 3 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 4 is selected from H and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
  • R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 F;
  • R 8 is selected from H and CH 3 ;
  • R a is each independently selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl and C 2-3 alkenyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl and C 2- 3 alkenyl are optionally substituted with 1, 2 or 3 F;
  • R b is each independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R c is each independently selected from 4-to 8-membered heterocycloalkyl, wherein the 4-to 8-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
  • R d is each independently selected from F, Cl, Br, I, OH, NH 2 and CN;
  • R is each independently selected from H, F, Cl, Br, OH, CN, C 1-3 alkyl, C 1-3 alkoxy and -C 1-3 alkyl-O-C ( ⁇ O) -C 1-3 alkylamino;
  • R 1 is naphthyl
  • the naphthyl is optionally substituted with F, Cl, Br, OH, NH2, CF 3 , CH 2 CH 3 and -C ⁇ CH
  • R 5 , R 6 and R 7 are each independently H.
  • the present application in another aspect provides a method of treating cancer in an individual, comprising administering to the individual an effective amount of 1) an ERK1/2 inhibitor; and 2) KRAS G12C inhibitor, wherein the KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from O and N;
  • R 1 is selected from C 6-10 aryl and 5-to 10-membered heteroaryl, wherein the C 6-10 aryl and 5-to 10-membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 R a ;
  • R 2 is selected from H, C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1- 3 alkyl, wherein the C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1-3 alkyl are optionally substituted with 1, 2 or 3 R b ;
  • R 3 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 4 is selected from H and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
  • R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 F;
  • R 8 is selected from H and CH 3 ;
  • R a is each independently selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl and C 2-3 alkenyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl and C 2- 3 alkenyl are optionally substituted with 1, 2 or 3 F;
  • R b is each independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R c is each independently selected from 4-to 8-membered heterocycloalkyl, wherein the 4-to 8-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
  • R d is each independently selected from F, Cl, Br, I, OH, NH 2 and CN;
  • R is each independently selected from H, F, Cl, Br, OH, CN, C 1-3 alkyl, C 1-3 alkoxy and -C 1-3 alkyl-O-C ( ⁇ O) -C 1-3 alkylamino;
  • R 1 is naphthyl
  • the naphthyl is optionally substituted with F, Cl, Br, OH, NH 2 , CF 3 , CH 2 CH 3 and -C ⁇ CH
  • R 5 , R 6 and R 7 are each independently H.
  • the KRAS G12C inhibitor comprises an agent comprising the following formula
  • the KRAS G12C inhibitor comprises an agent comprising the following formula
  • the ERK1/2 inhibitor is a small molecule.
  • the ERK1/2 inhibitor is selected from the group consisting of: BVD-523 (ulixertinib) , CC-90003, GDC-0994 (Ravoxertinib) , KO-947, LTT462, LY3214996 (temuterkib) , WX001, SCH772984, FR180204, and MK-8353.
  • the ERK1/2 inhibitor comprises an agent comprising the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1- 3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n 0 or 1
  • n 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1- 3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • the KRAS G12C inhibitor is administered orally. In some embodiments according to any of the methods described above, the ERK1/2 inhibitor is administered orally.
  • the cancer comprises one or more cancer cells that express a KRAS G12C mutant protein.
  • the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, mesothelioma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, Hodgkin lymphoma, myeloma, and sarcoma, optionally wherein the cancer is selected from the group consisting of colon cancer, lung cancer and pancreatic
  • the cancer was previously treated with a prior KRAS G12C inhibitor, optionally wherein the cancer was previously treated with two different prior KRAS G12C inhibitors.
  • the cancer is resistant to or has acquired resistance to a prior KRAS G12C inhibition, optionally wherein the cancer is resistant to or has acquired resistance to a prior KRAS G12C inhibitor (e.g., MRTX849, e.g., AMG510, e.g., Compound 17) .
  • the cancer is resistant to or has acquired resistance to two different prior KRAS G12C inhibitors.
  • the individual has acquired a secondary mutation in KRAS, optionally wherein the individual has acquired a secondary KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment, further optionally the individual has acquired a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T secondary mutation after the prior KRAS inhibitor treatment, further optionally wherein the secondary mutation comprises Q61H.
  • the cancer has an increased copy number of a mutant KRAS as compared to the cancer before the treatment of the prior KRAS G12C inhibition.
  • the individual develops a resistance to KRAS inhibitor that is independent from a MAPK pathway.
  • the prior KRAS G12C inhibitor is or comprises sotorasib or adagrasib.
  • the cancer was not previously treated with a prior KRAS G12C inhibitor.
  • the prior KRAS G12C inhibitor is or comprises sotorasib or adagrasib.
  • the ERK1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously or concurrently.
  • the ERK1/2 inhibitor and the KRAS G12C inhibitor are administered sequentially.
  • the ERK1/2 inhibitor is administered prior to the KRAS G12C inhibitor or b) the KRAS G12C inhibitor is administered prior to the ERK1/2 inhibitor.
  • the KRAS G12C inhibitor is administered orally, intravenously, or subcutaneously.
  • the ERK1/2 inhibitor is administered orally, intravenously, or subcutaneously.
  • the ERK 1/2 inhibitor is administered in one or more doses, optionally wherein the ERK 1/2 inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the dose is equivalent to a dose of about 10 mg/kg to about 100 mg/kg for a mouse, optionally wherein the dose is equivalent to a dose of about 10 mg/kg to about 50 mg/kg for a mouse.
  • the KRAS G12C inhibitor is administered in one or more doses, optionally wherein the KRAS G12C inhibitor is administered twice a day, daily or once every two days for at least 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the dose is equivalent to a dose of about 10 mg/kg to about 100 mg/kg for a mouse, optionally wherein the dose is equivalent to a dose of about 10 mg/kg to about 50 mg/kg for a mouse.
  • the third therapy comprises another anti-cancer agent.
  • the anti-cancer agent is selected from the group consisting of an immune checkpoint inhibitor, a cytotoxic agent, a cytostatic agent, an anti-angiogenic agent, a debulking agent, a chemotherapeutic agent, an antibody-drug conjugate, radiotherapy and radiotherapeutic agents, a targeted anti-cancer agent, BRMs, a therapeutic antibody, a cancer vaccine, cytokines, hormone therapies, radiation therapy, and anti-metastatic agents, optionally wherein the anti-cancer agent is an EGFR inhibitor, further optionally wherein the EGFR inhibitor is an anti-EGFR antibody, further optionally wherein the anti-EGFR antibody is cetuximab.
  • the individual is a human.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that comprises an aberration in KRAS (e.g., KRAS G12C, e.g., KRAS G12D, e.g., KRAS Q61H) , optionally wherein the aberration in KRAS comprises a) a KRAS G12C mutant protein, b) a KRAS G12D mutant protein and/or c) a KRAS Q61H mutant protein.
  • KRAS e.g., KRAS G12C, e.g., KRAS G12D, e.g., KRAS Q61H
  • the present application in another aspect provides a use of an ERK1/2 inhibitor and a KRAS G12C inhibitor for the manufacture of a medicament for treating cancer.
  • the cancer is selected from colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, mesothelioma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, Hodgkin lymphoma, myeloma, and sarcoma.
  • the cancer is colorectal cancer (e.g., NSCLC) . In some embodiments according to any of the methods described above, the cancer is pancreatic cancer. In some embodiments according to any of the methods described above, the cancer is lung cancer.
  • the treatment comprises a dose that is equivalent to a dose of 25 to 50 mg/kg of the ERK 1/2 inhibitor for a mouse.
  • the treatment comprises a dose that is equivalent to a dose of 10 to 100 mg/kg of the KRAS G12C inhibitor.
  • the present application in another aspect provides a kit for treating cancer in an individual, comprising: 1) an ERK1/2 inhibitor; and 2) a KRAS G12C inhibitor.
  • FIG. 1 shows the percentage of body weight change (%) .
  • FIG. 2 shows the tumor growth curves of different treatment groups of female BALB/c nude mice bearing NCI-H2122 xenograft tumors. Data points represent group mean; error bars represent standard error of the mean (SEM) .
  • FIG. 3 shows the tumor volumes of different treatment groups of female BALB/c nude mice bearing NCI-H2122 established tumors. Data points represent group mean; error bars represent standard error of the mean (SEM) .
  • FIG. 4 shows the weight of the tumors isolated from different treatment groups of female BALB/c nude mice bearing NCI-H2122 established tumors. Data points represent group mean; error bars represent standard error of the mean (SEM) .
  • FIG. 5 shows the percentage body weight change of each group over time in mice bearing SW-837 established tumors. Data points represent group mean; error bars represent standard error of the mean (SEM) .
  • FIG. 6A shows tumor growth curves of different treatment groups of mice bearing SW-837 xenograft tumors. Data points represent group mean; error bars represent the standard error of the mean (SEM) .
  • FIGs. 6B-6C show anti-tumor effect of various treatments in mice bearing SW837 xenografts and event-free survival during and after treatment.
  • FIG. 7 shows the tumor volume growth curves of different treatment groups of mice bearing CR9537 established tumors. Data points represent group mean; error bars represent standard error of the mean (SEM) .
  • FIG. 8 shows the percentage body weight change of each group over time in mice bearing CR9537 established tumors. Data points represent group mean; error bars represent standard error of the mean (SEM) .
  • FIG. 9 shows the body weight of different groups of female BALB/c nude mice bearing AMG510-R-xMia PaCa-2 clone #2 tumors. Data points represent group mean body weight. Error bars represent standard error of the mean (SEM) .
  • FIG. 10 shows percentage change of the body weight of different groups of female BALB/c nude mice bearing AMG510-R-xMia PaCa-2 clone #2 tumors. The change was calculated based on the animal weight of the first day of dosing. Data points represent percent group mean change in BW. Error bars represent standard error of the mean (SEM) .
  • FIG. 11 shows the tumor growth curves of different groups of female BALB/c nude mice bearing AMG510-R-xMia PaCa-2 clone #2 tumors. Data points represent group mean; error bars represent standard error of the mean (SEM) .
  • FIG. 12 shows data points represent the mouse survival curves (tumor size exceeding 1,000 mm 3 as an event) of different treatment groups of BALB/c nude mice bearing AMG510-R-xMia PaCa-2 clone #2 tumors.
  • FIG. 13 shows overall properties of WX001.
  • FIG. 14A shows that in overall Kinome selectivity profiling, WX001 demonstrated favorable selectivity in Eurofins Kinome panel of 430 kinases.
  • FIG. 14B and FIG. 14C show that in follow-up IC50 analysis, potential off-target kinases (>80%inhibition at 1uM concentration from Kinome profiling) were tested by dose-titration biochemical assays.
  • WX001 demonstrated >9.5 folds selectivity over GSK3 ⁇ and >10 folds selectivity over all other potential off-target kinases.
  • FIG. 15A shows inhibitory effect of WX001 on downstream signaling pathway determined by phosphorylated RSK assay in BRAF or KRAS mutant cancer cell lines.
  • FIG. 15B shows anti-proliferation effect of WX001 determined by Cell Titer-Glo method in BRAF or KRAS mutant cancer cell lines.
  • FIG. 16A shows tumor growth over time in NCI-H358 NSCLC cancer model treated with WX001 or BVD523, a reference ERK1/2 inhibitor.
  • FIG. 16B shows tumor growth over time in HCT-116 colorectal cancer model treated with WX001 or reference ERK1/2 inhibitors BVD523 and LY3214996.
  • FIG. 17A shows that NCI-H358 NSCLC tumor growth after treatment with KRAS G12C inhibitor monotherapy of MRTX849, AMG510 and Compound 17, or combination of Compound 17 and WX001.
  • FIG. 17B shows a summary of complete tumor remission rate in each treatment group.
  • FIG. 18 shows percentage of the body weight change of different treatment groups in female BALB/c nude mice bearing NCI-H1373 established tumors. The change was calculated based on the animal weight of the first day of dosing. Data points represent percent group mean change in BW. Error bars represent standard error of the mean (SEM) .
  • FIG. 19 shows body weight of different treatment groups in female BALB/c nude mice bearing NCI-H1373 established tumors. Data points represent group mean BW. Error bars represent standard error of the mean (SEM) .
  • FIG. 20 shows tumor growth curves of different treatment groups female BALB/c nude mice bearing NCI-H1373 established tumors. Data points represent group mean; error bars represent standard error of the mean (SEM) .
  • FIG. 21 shows tumor growth curves of different treatment groups female BALB/c nude mice bearing NCI-H1373 established tumors. Data points represent group mean; error bars represent standard error of the mean (SEM) .
  • the present application provides combination therapies for treating KRAS mutant cancer (e.g., KRAS G12C cancer) that comprises an ERK1/2 inhibitor and a KRAS inhibitor (e.g., KRAS G12C inhibitor) .
  • KRAS mutant cancer e.g., KRAS G12C cancer
  • the combination therapies provide advantageous and efficacious effects of treating KRAS mutant cancers (e.g., KRAS G12C cancers) while being safely tolerated.
  • aspects and embodiments of the present disclosure include “comprising, ” “consisting, ” and “consisting essentially of” aspects and embodiments.
  • treatment refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis.
  • an individual is successfully “treated” if one or more symptoms associated with cancer are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, and/or prolonging survival of individuals.
  • “treating” a disease such as cancer refers to delaying progression of the disease, i.e., deferring, hindering, slowing, retarding, stabilizing, and/or postponing development of the disease (such as cancer or a KRAS G12C cancer) .
  • This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated.
  • a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • a late-stage cancer such as development of metastasis, may be delayed.
  • an “effective amount” is at least the minimum amount required to effect a measurable improvement or prevention of a particular disease (e.g., cancer) .
  • An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of a therapeutic agent (or combination of therapeutic agents) to elicit a desired response in the individual.
  • An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects.
  • beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
  • an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder.
  • An effective amount can be administered in one or more administrations.
  • an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish therapeutic treatment either directly or indirectly.
  • an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.
  • an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
  • the term “subject” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc.
  • the mammal is human.
  • subject and “patient” are used interchangeably and include mammals such as humans and non-human primates, as well as rabbits, rats, mice, goats, pigs, and other mammalian species.
  • the term does not necessarily indicate that the subject has been diagnosed with a particular disease, but typically refers to an individual under medical supervision.
  • prevent refers generally to preventing or delaying the onset of the disease, or preventing the manifestation of clinical or subclinical symptoms thereof in a subject (whether a human or animal) , for example, preventing the disease from occurring in a subject predisposed to the condition or disease but has not yet been diagnosed as having it.
  • pharmaceutically acceptable means that the vehicle, diluent, excipient and/or salts thereof, are chemically and/or physically is compatible with other ingredients in the formulation, and the physiologically compatible with the recipient.
  • a pharmaceutically acceptable carrier and/or excipient refers to a carrier and/or excipient pharmacologically and/or physiologically compatible with a subject and an active agent, which is well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995) , and includes, but is not limited to pH adjuster, surfactant, adjuvant and ionic strength enhancer.
  • the pH adjuster includes, but is not limited to, phosphate buffer;
  • the surfactant includes, but is not limited to, cationic, anionic, or non-ionic surfactant, e.g., Tween-80;
  • the ionic strength enhancer includes, but is not limited to, sodium chloride.
  • adjuvant refers to a non-specific immunopotentiator, which can enhance immune response to an antigen or change the type of immune response in an organism when it is delivered together with the antigen to the organism or is delivered to the organism in advance.
  • adjuvants including, but not limited to, aluminium adjuvants (for example, aluminum hydroxide) , Freund’s adjuvants (for example, Freund’s complete adjuvant and Freund’s incomplete adjuvant) , coryne bacterium parvum, lipopolysaccharide, cytokines, and the like.
  • Freund's adjuvant is the most commonly used adjuvant in animal experiments now.
  • Aluminum hydroxide adjuvant is more commonly used in clinical trials.
  • the pharmaceutically acceptable salt disclosed herein can be prepared from the parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, such salt can be prepared by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture thereof.
  • Compounds disclosed herein may be present in a specific geometric or stereoisomeric form.
  • the present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereoisomer, (D) -isomer, (L) -isomer, and a racemic mixture and other mixtures, for example, a mixture enriched in enantiomer or diastereoisomer, all of which are encompassed within the scope disclosed herein.
  • the substituent such as alkyl may have an additional asymmetric carbon atom. All these isomers and mixtures thereof are encompassed within the scope disclosed herein.
  • Compounds disclosed herein may contain an unnatural proportion of atomic isotopes at one or more of the atoms that make up the compounds.
  • a compound may be labeled with a radioisotope such as tritium (3H) , iodine-125 (125I) or C-14 (14C) .
  • a radioisotope such as tritium (3H) , iodine-125 (125I) or C-14 (14C) .
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon.
  • deuterated drugs have advantages of reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life of drugs. All changes in the isotopic composition of compounds disclosed herein, regardless of radioactivity, are included within the scope of the present disclosure.
  • substituted means that one or more than one hydrogen atoms on a specific atom are substituted by a substituent, including deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable.
  • it means two hydrogen atoms are substituted.
  • Positions on an aromatic ring cannot be substituted by oxo.
  • optionally substituted means an atom can be substituted by a substituent or not, unless otherwise specified, the species and number of the substituent may be arbitrary so long as being chemically achievable.
  • variable such as R
  • the definition of the variable at each occurrence is independent.
  • the group can be optionally substituted by up to two R, wherein the definition of R at each occurrence is independent.
  • a combination of the substituent and/or the variant thereof is allowed only when the combination results in a stable compound.
  • linking group When the number of a linking group is 0, such as - (CRR) 0 -, it means that the linking group is a single bond.
  • one of variables is a single bond, it means that the two groups linked by the single bond are connected directly.
  • L in A-L-Z represents a single bond
  • the structure of A-L-Z is actually A-Z.
  • linking direction is arbitrary.
  • the linking group L in is -M-W-
  • the -M-W- can be linked to the ring A and the ring B in the same direction as the reading order from left to right to constitute or can be linked to the ring A and the ring B in the reverse direction as the reading order from left to right to constitute
  • substituents and/or variants thereof is allowed only when such combination can result in a stable compound.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection position of the chemical bond is variable, and there is H atom (s) at a connectable site (s)
  • the connectable site (s) having H atom (s) is connected to the chemical bond
  • the number of H atom (s) at this site will correspondingly decrease as the number of the connected chemical bond increases, and the group will become a group of corresponding valence.
  • the chemical bond between the site and other groups can be represented by a straight solid bond a straight dashed bond or a wavy line
  • the straight solid bond in -OCH 3 indicates that the group is connected to other groups through the oxygen atom in the group
  • the straight dashed bond in indicates that the group is connected to other groups through two ends of the nitrogen atom in the group
  • the wavy line in indicates that the group is connected to other groups through the 1-and 2-carbon atoms in the phenyl group
  • a wedged solid bond and a wedged dashed bond indicate the absolute configuration of a stereocenter; a straight solid bond and a straight dashed bond indicate the relative configuration of a stereocenter; a wavy line indicates a wedged solid bond or a wedged dashed bond or a wavy line indicates a straight solid bond and a straight dashed bond For example, represents represents represents
  • the term “enriched in one isomer” , “isomer enriched” , “enriched in one enantiomer” or “enantiomeric enriched” means that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is 60%or more, or 70%or more, or 80%or more, or 90%or more, or 95%or more, or 96%or more, or 97%or more, or 98%or more, or 99%or more, or 99.5%or more, or 99.6%or more, or 99.7%or more, or 99.8%or more, or 99.9%or more.
  • Optically active (R) -and (S) -isomer, or D and L isomer can be prepared using chiral synthesis or chiral reagents or other conventional techniques. If one kind of enantiomer of certain compound disclosed herein is to be obtained, the pure desired enantiomer can be obtained by asymmetric synthesis or derivative action of chiral auxiliary followed by separating the resulting diastereomeric mixture and cleaving the auxiliary group.
  • the compound when the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxyl) , the compound reacts with an appropriate optically active acid or base to form a salt of the diastereomeric isomer which is then subjected to diastereomeric resolution through the conventional method in the art to afford the pure enantiomer.
  • the enantiomer and the diastereoisomer are generally isolated through chromatography which uses a chiral stationary phase and optionally combines with a chemical derivative method (for example, carbamate generated from amine) .
  • C1-6 alkyl is used to represent a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C1-6 alkyl includes C1-5, C1-4, C1-3, C1-2, C2-6, C2-4, C6, and C5 alkyl, etc. It may be monovalent (such as methyl) , divalent (such as methylene) or multivalent (such as methenyl) .
  • Examples of the C1-6 alkyl include, but are not limited to, methyl (Me) , ethyl (Et) , propyl (including n-propyl and isopropyl) , butyl (including n-butyl, isobutyl, s-butyl and t-butyl) , pentyl (including n-pentyl, isopentyl and neopentyl) , hexyl, and the like.
  • C1-3 alkyl is used to represent a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C1-3 alkyl includes C1-2 alkyl, C2-3 alkyl, etc. It may be monovalent (such as methyl) , divalent (such as methylene) or multivalent (such as methenyl) .
  • Examples of the C1-3 alkyl include, but are not limited to, methyl (Me) , ethyl (Et) , propyl (including n-propyl and isopropyl) , and the like.
  • C1-3 alkoxy means alkyl groups containing 1 to 3 carbon atoms and attached to the remainder of a molecule by an oxygen atom.
  • the C1-3 alkoxy group includes C1-2, C2-3, C3, and C2 alkoxy groups, and the like.
  • Examples of C1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) , and the like.
  • C1-3 alkylamino means alkyl groups containing 1 to 3 carbon atoms and attached to the remainder of a molecule by an amino group.
  • the C1-3 alkylamino group includes C1-2, C3 and C2 alkylamino groups and the like.
  • Examples of C1-3 alkylamino groups include, but are not limited to -NHCH3, -N (CH3) 2, -NHCH2CH3, -N (CH3) CH2CH3, -NHCH2CH2CH3, -NHCH2 (CH3) 2, and the like.
  • C2-3 alkenyl is used to represent a linear or branched hydrocarbon group composed of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, wherein the carbon-carbon double bond can be located at any position of the group.
  • the C2-3 alkenyl includes C3 and C2 alkenyl.
  • the C2-3 alkenyl may be monovalent, divalent or multivalent. Examples of the C2-3 alkenyl include, but are not limited to, vinyl, propenyl, and the like.
  • C2-3 alkynyl is used to represent a linear or branched hydrocarbon group composed of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond can be located at any position of the group.
  • the C2-3 alkynyl includes C3 and C2 alkynyl. Examples of the C2-3 alkynyl include, but are not limited to, ethynyl, propynyl, and the like.
  • C6-10 aromatic ring and “C6-10 aryl” may be used interchangeably in this disclosure.
  • the term"C6-10 aromatic ring” or “C6-10 aryl” means a cyclic hydrocarbon group having a conjugated pi electron system and composed of 6 to 10 carbon atoms. It may be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. It may be monovalent, divalent or multivalent.
  • the C6-10 aryl includes C6-9, C9, C10 and C6 aryl, etc. Examples of C6-10 aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc. ) .
  • 5-to 10-membered heteroaromatic ring and “5-to 10-membered heteroaryl” may be used interchangeably.
  • the term “5-to 10-membered heteroaryl” means a cyclic group having a conjugated pi electron system and composed of 5 to 10 ring atoms, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the remainder is carbon atoms.
  • a 5-to 10-membered heteroaryl can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • the 5-to 10-membered heteroaryl group includes 5-to 8-membered, 5-to 7-membered, 5-to 6-membered, 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-10 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, and the like) , pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, and the like) , imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, and the like) , oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, and the like) , triazolyl (1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, 1H-1, 2, 4-triazolyl and 4H-1, 2, 4-triazolyl, and the like) , tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, and the like) ,
  • the term "4-to 8-membered heterocycloalkyl” alone or in combination with other terms respectively represents a saturated cyclic group composed of 4 to 8 ring atoms, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S (O) p, p is 1 or 2) .
  • the ring comprises monocyclic and bicyclic ring systems, wherein the bicyclic ring systems comprise spiro, fused, and bridged cyclic rings.
  • the heteroatom may be present on the position of attachment of the heterocycloalkyl group to the remainder of a molecule.
  • the 4-to 8-membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl, etc.
  • Examples of the 4-to 8-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl and the like) , tetrahydrofuranyl (including tetrahydrofuran-2-yl and the like) , tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl and the like) , piperazinyl (including 1-piperazinyl and 2-piperazinyl and the like) , morpholinyl (including 3-morpholinyl and 4-morpholinyl and the like) , dioxanyl, dithianyl, isoxazolidin
  • Cn-n+m or Cn-Cn+m includes any specific case of n to n+m carbons, for example, C1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12, also includes any range from n to n+m, for example, C1-12 includes C1-3, C1-6, C1-9, C3-6, C3-9, C3-12, C6-9, C6-12 and C9-12, etc.; similarly, n membered to n+m membered indicates that the number of atoms on a ring is n to n+m, for example, 3-12 membered ring includes 3 membered ring, 4 membered ring, 5 membered ring, 6 membered ring, 7 membered ring, 8 membered ring, 9 membered ring, 10 membered ring, 11 membered ring, and 12 membered ring, also includes any range from n to n+m carbons
  • the absolute configuration can be confirmed by conventional techniques in the art, such as single crystal X-Ray diffraction (SXRD) .
  • SXRD single crystal X-Ray diffraction
  • the diffraction intensity data of the cultivated single crystal is collected using a Bruker D8 venture diffractometer with a light source of CuK ⁇ radiation in a scanning mode of scan; after collecting the relevant data, the crystal structure is further analyzed by the direct method (Shelxs97) to confirm the absolute configuration.
  • Solvents used in the present disclosure are commercially available.
  • the pharmaceutically acceptable salt disclosed herein can be prepared from the parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, such salt can be prepared by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture thereof.
  • a KRAS G12C mutation i.e., a cancer comprising one or more cancer cells that express a KRAS G12C mutant protein
  • administering comprising administering to the subject an effective amount of (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor.
  • the ERK1/2 inhibitor is used for the manufacture of a medicament for treating cancer, wherein the treatment is in combination with a KRAS G12C inhibitor.
  • the ERK 1/2 inhibitor is, e.g., a small molecule, a polypeptide (such as an antibody) , a peptide, an antisense oligonucleotide that inhibits the activity of the ERK1 and/or ERK2 protein.
  • exemplary small molecule ERK 1/2 inhibitors that find use with the methods provided herein include, without limitation, e.g., BVD-523 (ulixertinib) , CC-90003, GDC-0994 (Ravoxertinib) , KO-947, LTT462, LY3214996 (temuterkib) , WX001, SCH772984, FR180204, MK-8353.
  • the KRAS G12C inhibitor is a small molecule.
  • Exemplary small molecule KRAS G12C inhibitors that find use with the methods provided herein include, without limitation, e.g., Compound 17, sotorasib, adagrasib, JAB-21822, GDC-6036, JDQ443, D-1553, GH35, GFH925, BPI-421286, and LY3537982, RMC-6291, HBI-2438, and JNJ-74699157.
  • the KRAS G12C inhibitor is Compound 17. Additional details regarding these and other exemplary small molecule KRAS G12C inhibitors are described in further detail below.
  • a method of treating cancer e.g., a cancer comprising one or more cancer cells that express a KRAS G12C mutant protein, e.g., a cancer resistant to a prior KRAS G12C inhibitor
  • an individual e.g., a human patient
  • administering to the individual (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor.
  • the ERK 1/2 inhibitor is a small molecule.
  • the ERK 1/2 inhibitor is administered orally.
  • the KRAS G12C inhibitor is a small molecule.
  • the KRAS G12C inhibitor is administered orally.
  • the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, mesothelioma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, Hodgkin lymphoma, myeloma, and sarcoma.
  • the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is advanced, unresectable, and/or metastatic solid tumor. In some embodiments, the cancer is to KRAS G12C inhibition treatment. In some embodiments, the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially. In some embodiments, the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method further comprises administering to the individual an effective amount of a third therapy comprising another anti-cancer agent, optionally wherein the anti-cancer agent is selected from the group consisting of an immune checkpoint inhibitor, a cytotoxic agent, a cytostatic agent, an anti-angiogenic agent, a debulking agent, a chemotherapeutic agent, an antibody-drug conjugate, radiotherapy and radiotherapeutic agents, a targeted anti-cancer agent, BRMs, a therapeutic antibody, a cancer vaccine, cytokines, hormone therapies, radiation therapy, and anti-metastatic agents.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • a method of treating cancer e.g., a cancer comprising one or more cancer cells that express a KRAS G12C mutant protein, e.g., a cancer resistant to a prior KRAS G12C inhibitor
  • an individual e.g., a human patient
  • administering to the individual (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor.
  • the ERK 1/2 inhibitor is a small molecule.
  • the ERK 1/2 inhibitor is administered orally.
  • the KRAS G12C inhibitor is a small molecule.
  • the KRAS G12C inhibitor is administered orally.
  • the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, mesothelioma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, Hodgkin lymphoma, myeloma, and sarcoma.
  • the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is advanced, unresectable, and/or metastatic solid tumor. In some embodiment, the cancer (e.g., cancer cells) is only partially responding to the prior KRAS treatment.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially. In some embodiments, the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method further comprises administering to the individual an effective amount of a third therapy comprising another anti-cancer agent, optionally wherein the anti-cancer agent is selected from the group consisting of an immune checkpoint inhibitor, a cytotoxic agent, a cytostatic agent, an anti-angiogenic agent, a debulking agent, a chemotherapeutic agent, an antibody-drug conjugate, radiotherapy and radiotherapeutic agents, a targeted anti-cancer agent, BRMs, a therapeutic antibody, a cancer vaccine, cytokines, hormone therapies, radiation therapy, and anti-metastatic agents.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • a method of treating cancer e.g., a cancer comprising one or more cancer cells that express a KRAS G12C mutant protein, e.g., a cancer resistant to a prior KRAS G12C inhibitor
  • an individual e.g., a human patient
  • administering to the individual (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor.
  • the ERK 1/2 inhibitor is a small molecule.
  • the ERK 1/2 inhibitor is administered orally.
  • the KRAS G12C inhibitor is a small molecule.
  • the KRAS G12C inhibitor is administered orally.
  • the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, mesothelioma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, Hodgkin lymphoma, myeloma, and sarcoma.
  • the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is advanced, unresectable, and/or metastatic solid tumor. In some embodiments, the cancer is resistant to (e.g., has acquired resistance to) KRAS G12C inhibition (e.g., resistant to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, or Compound 17) . In some embodiments, the cancer was previously treated with a KRAS G12C inhibitor. In some embodiments, the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • KRAS G12C inhibition e.g., resistant to MRTX849, AMG510, or Compound 17
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • the individual develops a resistance to KRAS inhibitor that is independent from a MAPK pathway.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method further comprises administering to the individual an effective amount of a third therapy comprising another anti-cancer agent, optionally wherein the anti-cancer agent is selected from the group consisting of an immune checkpoint inhibitor, a cytotoxic agent, a cytostatic agent, an anti-angiogenic agent, a debulking agent, a chemotherapeutic agent, an antibody-drug conjugate, radiotherapy and radiotherapeutic agents, a targeted anti-cancer agent, BRMs, a therapeutic antibody, a cancer vaccine, cytokines, hormone therapies, radiation therapy, and anti-metastatic agents.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the cancer further comprises a KRAS Q61H mutation.
  • the KRAS Q61H mutation is acquired after a prior therapy (e.g., a KRAS G12C therapy) .
  • a method of treating cancer comprising administering to the individual (1) an ERK1/2 inhibitor; and (2) KRAS G12C inhibitor, wherein the ERK 1/2 inhibitor comprises an agent comprising formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n is 0 or 1;
  • m is 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R d ;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • the ERK 1/2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is advanced, unresectable, and/or metastatic solid tumor. In some embodiments, the cancer is resistant (e.g., has acquired resistance to) to KRAS G12C inhibition (e.g., resistant to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, or Compound 17) . In some embodiments, the cancer was previously treated with a second KRAS G12C inhibitor.
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • the individual develops a resistance to KRAS inhibitor that is independent from a MAPK pathway.
  • the second KRAS inhibitor is sotorasib or adagrasib.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the KRAS Q61H mutation is acquired after a prior therapy (e.g., a KRAS G12C therapy) .
  • a method of treating cancer comprising administering to the individual (1) an ERK1/2 inhibitor; and (2) KRAS G12C inhibitor, wherein the ERK 1/2 inhibitor is selected from the following formulas or a pharmaceutically acceptable salt thereof,
  • the ERK 1/2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is advanced, unresectable, and/or metastatic solid tumor. In some embodiments, the cancer is resistant to (e.g., has acquired resistance to) KRAS G12C inhibition (e.g., resistant to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, or Compound 17) . In some embodiments, the cancer was previously treated with a second KRAS G12C inhibitor.
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • the individual develops a resistance to KRAS inhibitor that is independent from a MAPK pathway.
  • the second KRAS inhibitor is sotorasib or adagrasib.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the KRAS Q61H mutation is acquired after a prior therapy (e.g., a KRAS G12C therapy) .
  • a method of treating cancer comprising administering to the individual (1) an ERK1/2 inhibitor; and (2) KRAS G12C inhibitor, wherein the ERK 1/2 inhibitor is the following formula or a pharmaceutically acceptable salt thereof,
  • the ERK 1/2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is advanced, unresectable, and/or metastatic solid tumor. In some embodiments, the cancer is resistant to (e.g., has acquired resistance to) KRAS G12C inhibition (e.g., resistant to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, Compound 17) . In some embodiments, the cancer was previously treated with a second KRAS G12C inhibitor.
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • the individual develops a resistance to KRAS inhibitor that is independent from a MAPK pathway.
  • the second KRAS inhibitor is sotorasib or adagrasib.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the KRAS Q61H mutation is acquired after a prior therapy (e.g., a KRAS G12C therapy) .
  • a method of treating cancer comprising administering to the individual (1) an ERK1/2 inhibitor; and (2) KRAS G12C inhibitor, wherein the KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from O and N; R 1 is selected from C6-10 aryl and 5-to 10-membered heteroaryl, wherein the C6-10 aryl and 5-to 10-membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 R a ; when T1 is O, R 2 is not present; when T1 is N, R 2 is selected from H, C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C1-3 alkyl, wherein the C1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1-3 alkyl are optionally substituted with 1, 2 or 3 R b ; R 3 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ; R 4 is selected from H and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or
  • the ERK 1/2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is advanced, unresectable, and/or metastatic solid tumor. In some embodiments, the cancer is resistant to (e.g., has acquired resistance to) KRAS G12C inhibition (e.g., resistant to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, Compound 17) . In some embodiments, the cancer was previously treated with a second KRAS G12C inhibitor.
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • the individual develops a resistance to KRAS inhibitor that is independent from a MAPK pathway.
  • the second KRAS inhibitor is sotorasib or adagrasib.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the KRAS Q61H mutation is acquired after a prior therapy (e.g., a KRAS G12C therapy) .
  • a method of treating cancer comprising administering to the individual (1) an ERK1/2 inhibitor; and (2) KRAS G12C inhibitor, wherein the KRAS G12C inhibitor comprises an agent comprising the following formulas or a pharmaceutically acceptable salt thereof,
  • the ERK 1/2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is advanced, unresectable, and/or metastatic solid tumor. In some embodiments, the cancer is resistant to (e.g., has acquired resistance to) KRAS G12C inhibition (e.g., resistant to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, Compound 17) . In some embodiments, the cancer was previously treated with a second KRAS G12C inhibitor.
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • the individual develops a resistance to KRAS inhibitor that is independent from a MAPK pathway.
  • the second KRAS inhibitor is sotorasib or adagrasib.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the KRAS Q61H mutation is acquired after a prior therapy (e.g., a KRAS G12C therapy) .
  • a method of treating cancer comprising administering to the individual (1) an ERK1/2 inhibitor; and (2) KRAS G12C inhibitor, wherein the KRAS G12C inhibitor comprises an agent comprising formula or a pharmaceutically acceptable salt thereof,
  • the ERK 1/2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is advanced, unresectable, and/or metastatic solid tumor. In some embodiments, the cancer is resistant to (e.g., has acquired resistance to) KRAS G12C inhibition (e.g., resistant to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, Compound 17) . In some embodiments, the cancer was previously treated with a second KRAS G12C inhibitor.
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • the individual develops a resistance to KRAS inhibitor that is independent from a MAPK pathway.
  • the second KRAS inhibitor is sotorasib or adagrasib.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the KRAS Q61H mutation is acquired after a prior therapy (e.g., a KRAS G12C therapy) .
  • a method of treating cancer comprising administering to the individual (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the ERK 1/2 inhibitor comprises an agent comprising formula (I) or a pharmaceutically acceptable salt thereof,
  • R1 and R2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 Ra ;
  • R4 , R5 , R6 and R7 are independently selected from H, F, Cl, Br, I and C1-3 alkyl, and the C1-3 alkyl is optionally replaced by 1, 2 or 3 Rc substitution;
  • n is 0 or 1;
  • m is 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 Rd;
  • Ra and Rc are independently selected from D, F, Cl, Br and I;
  • Rd is selected from F, Cl, Br, I, C1-3 alkyl and C1-3 alkoxy, and said C1-3 alkyl and C1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I; and wherein the KRAS G12C inhibitor comprises an agent comprising formula (
  • T 1 is selected from O and N; R 1 is selected from C 6-10 aryl and 5-to 10-membered heteroaryl, wherein the C6-10 aryl and 5-to 10-membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 R a ; when T 1 is O, R 2 is not present; when T 1 is N, R 2 is selected from H, C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1-3 alkyl, wherein the C 1-3 alkyl, -C ( ⁇ O) -C1-3 alkyl and -S ( ⁇ O) 2 -C 1-3 alkyl are optionally substituted with 1, 2 or 3 R b ; R 3 is C1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ; R 4 is selected from H and C 1-3 alkyl, wherein the C 1- 3 alkyl is optionally substituted with 1, 2 or
  • the ERK 1/2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is advanced, unresectable, and/or metastatic solid tumor. In some embodiments, the cancer is resistant to (e.g., has acquired resistance to) KRAS G12C inhibition (e.g., resistant to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, or Compound 17) . In some embodiments, the cancer was previously treated with a second KRAS G12C inhibitor.
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • the individual develops a resistance to KRAS inhibitor that is independent from a MAPK pathway.
  • the second KRAS inhibitor is sotorasib or adagrasib.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the KRAS Q61H mutation is acquired after a prior therapy (e.g., a KRAS G12C therapy) .
  • a method of treating cancer e.g., a cancer comprising one or more cancer cells that express a KRAS G12C mutant protein, e.g., a cancer resistant to a prior KRAS G12C inhibitor
  • an individual e.g., a human patient
  • administering comprising administering to the individual (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor.
  • ERK 1/2 inhibitor comprises an agent comprising formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n is 0 or 1;
  • m is 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R d ;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I; and wherein
  • the ERK 1/2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is advanced, unresectable, and/or metastatic solid tumor. In some embodiments, the cancer is resistant to (e.g., has acquired resistance to) KRAS G12C inhibition (e.g., resistant to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, Compound 17) . In some embodiments, the cancer was previously treated with a second KRAS G12C inhibitor.
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • the individual develops a resistance to KRAS inhibitor that is independent from a MAPK pathway.
  • the second KRAS inhibitor is sotorasib or adagrasib.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method further comprises administering to the individual an effective amount of a third therapy comprising another anti-cancer agent, optionally wherein the anti-cancer agent is selected from the group consisting of an immune checkpoint inhibitor, a cytotoxic agent, a cytostatic agent, an anti-angiogenic agent, a debulking agent, a chemotherapeutic agent, an antibody-drug conjugate, radiotherapy and radiotherapeutic agents, a targeted anti-cancer agent, BRMs, a therapeutic antibody, a cancer vaccine, cytokines, hormone therapies, radiation therapy, and anti-metastatic agents.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the KRAS Q61H mutation is acquired after a prior therapy (e.g., a KRAS G12C therapy) .
  • a method of treating cancer e.g., a cancer comprising one or more cancer cells that express a KRAS G12C mutant protein, e.g., a cancer resistant to a prior KRAS G12C inhibitor
  • an individual e.g., a human patient
  • administering comprising administering to the individual (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the ERK 1/2 inhibitor comprises an agent comprising the following formula or a pharmaceutically acceptable salt thereof,
  • KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof
  • the ERK 1/2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is advanced, unresectable, and/or metastatic solid tumor. In some embodiments, the cancer is resistant to (e.g., has acquired resistance to) KRAS G12C inhibition (e.g., resistant to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, or Compound 17) . In some embodiments, the cancer was previously treated with a second KRAS G12C inhibitor.
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • the individual develops a resistance to KRAS inhibitor that is independent from a MAPK pathway.
  • the second KRAS inhibitor is sotorasib or adagrasib.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the KRAS Q61H mutation is acquired after a prior therapy (e.g., a KRAS G12C therapy) .
  • a method of treating cancer e.g., a cancer comprising one or more cancer cells that express a KRAS G12C mutant protein, e.g., a cancer resistant to a prior KRAS G12C inhibitor
  • an individual e.g., a human patient
  • administering comprising administering to the individual (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the ERK 1/2 inhibitor comprises an agent comprising the following formula or a pharmaceutically acceptable salt thereof,
  • KRAS G12C inhibitor comprises an agent comprising the following formula or a pharmaceutically acceptable salt thereof
  • the ERK 1/2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is advanced, unresectable, and/or metastatic solid tumor. In some embodiments, the cancer is resistant to (e.g., has acquired resistance to) KRAS G12C inhibition (e.g., resistant to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, or Compound 17) . In some embodiments, the cancer was previously treated with a second KRAS G12C inhibitor.
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • the individual develops a resistance to KRAS inhibitor that is independent from a MAPK pathway.
  • the second KRAS inhibitor is sotorasib or adagrasib.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the KRAS Q61H mutation is acquired after a prior therapy (e.g., a KRAS G12C therapy) .
  • a method of treating a lung cancer e.g., a NSCLC comprising a KRAS G12C mutation, e.g., a NSCLC cancer with a KRAS G12C mutation that is sensitive to an anti-EGFR therapy
  • a lung cancer e.g., a NSCLC comprising a KRAS G12C mutation, e.g., a NSCLC cancer with a KRAS G12C mutation that is sensitive to an anti-EGFR therapy
  • an individual e.g., a human patient
  • administering comprising administering to the individual (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor.
  • a method of treating a lung cancer e.g., a lung cancer that is resistant to a KRAS G12C inhibitor
  • an individual e.g., a human patient
  • administering comprising administering to the individual (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor.
  • the dose of KRAS G12C inhibitor is equivalent to a dose of 30-100 mg/kg (e.g., no more than 50 mg/kg, 40 mg/kg or 30 mg/kg) for a mouse, optionally wherein the KRAS G12C inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the dose of an ERK 1/2 inhibitor is equivalent to a dose of about 25-50 mg/kg (e.g., a daily dose of about or at least about 50 mg/kg) for a mouse, optionally wherein the ERK1/2 inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the ERK 1/2 inhibitor formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n is 0 or 1;
  • m is 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R d ;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • the KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof,
  • the KRAS G12C inhibitor is selected from the group consisting of Compound 17, MRTX849, and AMG510.
  • the KRAS G12C inhibitor comprises an agent (Compound 17) comprising the following formula or a pharmaceutically acceptable salt thereof,
  • the cancer is resistant to (e.g., has acquired resistance to) KRAS G12C inhibition (e.g., resistant to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, or Compound 17) .
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment. In some embodiments, the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • a method of treating a colorectal cancer e.g., a colorectal cancer comprising a KRAS G12C mutation, e.g., a colorectal cancer with a KRAS G12C mutation that is resistant to a prior KRAS G12C therapy
  • a colorectal cancer e.g., a colorectal cancer comprising a KRAS G12C mutation, e.g., a colorectal cancer with a KRAS G12C mutation that is resistant to a prior KRAS G12C therapy
  • an individual e.g., a human patient
  • administering comprising administering to the individual (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor.
  • the dose of KRAS G12C inhibitor is equivalent to a dose of 10-100 mg/kg (e.g., no more than 30 mg/kg, 20 mg/kg or 10 mg/kg) for a mouse, optionally wherein the KRAS G12C inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the dose of an ERK 1/2 inhibitor is equivalent to a dose of about 25-50 mg/kg (e.g., a daily dose of about or at least about 50 mg/kg or 25 mg/kg) for a mouse, optionally wherein the ERK1/2 inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the method further comprises administering an EGFR inhibitor (e.g., an anti-EGFR antibody, e.g., cetuximab) .
  • the dose of the EGFR inhibitor is equivalent to about 30 mg/kg for a mouse.
  • the EGFR inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the ERK 1/2 inhibitor, the KRAS G12C inhibitor, and/or the EGFR inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the ERK 1/2 inhibitor is administered prior to the EGFR inhibitor.
  • the EGFR inhibitor is administered prior to the ERK 1/2 inhibitor. In some embodiments, the EGFR inhibitor is administered prior to the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered prior to the EGFR inhibitor. In some embodiments, the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein. In some embodiments, the ERK 1/2 inhibitor formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n is 0 or 1;
  • m is 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R d ;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • the KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof,
  • the KRAS G12C inhibitor is selected from the group consisting of Compound 17, MRTX849, and AMG510. In some embodiments, the KRAS G12C inhibitor comprises an agent comprising the following formula or a pharmaceutically acceptable salt thereof,
  • the cancer has acquired resistance to KRAS G12C inhibition (e.g., has acquired resistance to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, or Compound 17) .
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment. In some embodiments, the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • a method of treating a colorectal cancer comprising a KRAS G12C mutation and a Q61H mutation
  • a colorectal cancer e.g., a colorectal cancer comprising a KRAS G12C mutation and a Q61H mutation
  • an individual e.g., a human patient
  • administering comprising administering to the individual (1) an ERK 1/2 inhibitor (e.g., WX001) ; and (2) a KRAS G12C inhibitor (e.g., MRTX849, e.g., Compound 17) .
  • an ERK 1/2 inhibitor e.g., WX001
  • a KRAS G12C inhibitor e.g., MRTX849, e.g., Compound 17
  • a method of treating a colorectal cancer e.g., a colorectal cancer comprising a KRAS G12C mutation and a Q61H mutation
  • an individual e.g., a human patient
  • administering comprising administering to the individual (1) an ERK 1/2 inhibitor (e.g., WX001) ; and (2) MRTX849.
  • an ERK 1/2 inhibitor e.g., WX001
  • MRTX849 MRTX849.
  • a method of treating a colorectal cancer e.g., a colorectal cancer comprising a KRAS G12C mutation and a Q61H mutation
  • an individual e.g., a human patient
  • administering to the individual (1) an ERK 1/2 inhibitor (e.g., WX001) ; and (2) Compound 17.
  • the Q61H mutation is acquired after resistance to a prior KRAS inhibitor (e.g., a prior KRAS G12C inhibitor) .
  • the dose of KRAS G12C inhibitor is equivalent to a dose of 30-100 mg/kg (e.g., no more than 50 mg/kg, 40 mg/kg or 30 mg/kg) for a mouse, optionally wherein the KRAS G12C inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the dose of an ERK 1/2 inhibitor is equivalent to a dose of about 25-50 mg/kg (e.g., a daily dose of about or at least about 50 mg/kg) for a mouse, optionally wherein the ERK1/2 inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the ERK 1/2 inhibitor formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n is 0 or 1;
  • m is 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R d ;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • the KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof,
  • the KRAS G12C inhibitor is selected from the group consisting of Compound 17, MRTX849, and AMG510.
  • the KRAS G12C inhibitor comprises an agent comprising the following formula or a pharmaceutically acceptable salt thereof.
  • the cancer has acquired resistance to KRAS G12C inhibition (e.g., has acquired resistance to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, or Compound 17) .
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • a method of treating a pancreatic cancer e.g., a pancreatic cancer comprising a KRAS G12C mutation, e.g., a pancreatic cancer with a KRAS G12C mutation that is resistant to a prior KRAS G12C inhibitor
  • a pancreatic cancer e.g., a pancreatic cancer comprising a KRAS G12C mutation, e.g., a pancreatic cancer with a KRAS G12C mutation that is resistant to a prior KRAS G12C inhibitor
  • an individual e.g., a human patient
  • administering comprising administering to the individual (1) an ERK 1/2 inhibitor (e.g., WX001) ; and (2) a KRAS G12C inhibitor (e.g., MRTX849, e.g., Compound 17) .
  • an ERK 1/2 inhibitor e.g., WX001
  • a KRAS G12C inhibitor e.g., MRT
  • the dose of KRAS G12C inhibitor is equivalent to a dose of 30-100 mg/kg (e.g., no more than 50 mg/kg, 40 mg/kg or 30 mg/kg) for a mouse, optionally wherein the KRAS G12C inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the dose of an ERK 1/2 inhibitor is equivalent to a dose of about 25-50 mg/kg (e.g., a daily dose of about or at least about 50 mg/kg) for a mouse, optionally wherein the ERK1/2 inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the ERK 1/2 inhibitor formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n is 0 or 1;
  • m is 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R d ;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • the KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof,
  • the KRAS G12C inhibitor is selected from the group consisting of Compound 17, MRTX849, and AMG510.
  • the KRAS G12C inhibitor comprises an agent comprising the following formula or a pharmaceutically acceptable salt thereof.
  • the cancer has acquired resistance to KRAS G12C inhibition (e.g., has acquired resistance to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, or Compound 17) .
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • a method of treating a cancer harboring a KRAS G12C mutation in an individual comprising administering to the individual (1) an ERK 1/2 inhibitor; (2) a KRAS G12C inhibitor and (3) an EGFR inhibitor.
  • the cancer does not have any additional KRAS mutation or aberration.
  • the cancer does not have any acquired secondary KRAS mutation.
  • the EGFR inhibitor is an EGFR antibody (e.g., cetuximab) .
  • the cancer is a lung cancer, a colorectal cancer, or a pancreatic cancer.
  • the dose of KRAS G12C inhibitor is equivalent to a dose of 30-100 mg/kg (e.g., no more than 50 mg/kg, 40 mg/kg or 30 mg/kg) for a mouse, optionally wherein the KRAS G12C inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the dose of an ERK 1/2 inhibitor is equivalent to a dose of about 25-50 mg/kg (e.g., a daily dose of about or at least about 50 mg/kg) for a mouse, optionally wherein the ERK1/2 inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the ERK 1/2 inhibitor formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n is 0 or 1;
  • m is 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R d ;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • the KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof,
  • the KRAS G12C inhibitor is selected from the group consisting of Compound 17, MRTX849, and AMG510. In some embodiments, the KRAS G12C inhibitor comprises an agent comprising the following formula or a pharmaceutically acceptable salt thereof,
  • a method of treating a cancer harboring a KRAS G12C mutation in an individual comprising administering to the individual (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor, wherein the cancer has at least one additional KRAS aberration other than G12C mutation.
  • the additional KRAS aberration is an acquired secondary aberration after a prior therapy (e.g., a prior KRAS G12C inhibitor described here) .
  • the additional KRAS aberration is a germline aberration or mutation.
  • the additional KRAS aberration is selected from the group consisting of a G12D, G12R, G12V, G12W, G13D, A59T, Q61H, R68S, R68M, H95D, H95Q, H95R, Y96C, Y96D, and high-level amplification of the KRASG12C allele.
  • the cancer is a lung cancer, a colorectal cancer, or a pancreatic cancer.
  • the dose of KRAS G12C inhibitor is equivalent to a dose of 30-100 mg/kg (e.g., no more than 50 mg/kg, 40 mg/kg or 30 mg/kg) for a mouse, optionally wherein the KRAS G12C inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the dose of an ERK 1/2 inhibitor is equivalent to a dose of about 25-50 mg/kg (e.g., a daily dose of about or at least about 50 mg/kg) for a mouse, optionally wherein the ERK1/2 inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that express a KRAS G12C mutant protein.
  • the ERK 1/2 inhibitor formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n is 0 or 1;
  • m is 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R d ;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • the KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof,
  • the KRAS G12C inhibitor is selected from the group consisting of Compound 17, MRTX849, and AMG510. In some embodiments, the KRAS G12C inhibitor comprises an agent comprising the following formula or a pharmaceutically acceptable salt thereof,
  • the subject is a human (e.g. a human patient) .
  • Cancer described herein include any kind of cancer that has a KRAS G12C mutation.
  • a cancer (or a population of cancer cells) that comprises one or more cancer cells that express a KRAS G12C mutant protein is alternatively referred to herein as “aKRAS G12C mutant cancer.
  • the cancer (such as the KRAS G12C mutant cancer) is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, mesothelioma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, Hodgkin lymphoma, myeloma, and sarcoma.
  • the cancer is lung cancer.
  • the cancer is colorectal cancer.
  • the cancer is pancreatic cancer.
  • the cancer is an advanced, un
  • the ERK 1/2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally.
  • the construct and the KRAS G12C inhibitor are administered simultaneously.
  • “simultaneous administration” means that the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered with a time separation of no more than about 15 minute (s) , such as no more than about any of 10, 5, or 1 minutes.
  • simultaneous administration of the ERK 1/2 inhibitor and the KRAS G12C inhibitor can be combined with supplemental doses of the ERK 1/2 inhibitor and/or the KRAS G12C inhibitor.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered sequentially.
  • “sequential administration” means that the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60 or more minutes.
  • the ERK 1/2 inhibitor is administered prior to the small molecule KRAS G12C inhibitor.
  • the small molecule KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the administration of the ERK 1/2 inhibitor and the KRAS G12C inhibitor are concurrent, i.e., the administration period of the ERK 1/2 inhibitor and the KRAS G12C inhibitor overlap with each other.
  • the administration of the ERK 1/2 inhibitor and the KRAS G12C inhibitor are non-concurrent.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the methods disclosed herein further comprise administering an effective amount of a third therapy.
  • the third therapy is another anti-cancer agent.
  • anti-cancer agent or “anti-proliferative agent” means any agent that can be used to treat a cell proliferative disorder such as cancer, and includes, but is not limited to, cytotoxic agents, cytostatic agents, anti-angiogenic agents, debulking agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, BRMs, therapeutic antibodies, cancer vaccines, cytokines, hormone therapies, radiation therapy and anti-metastatic agents and immunotherapeutic agents.
  • anti-cancer agents may comprise conjugates and may be associated with the disclosed antibodies prior to administration. More specifically, in certain embodiments selected anti-cancer agents will be linked to the unpaired cysteines of the engineered antibodies to provide engineered conjugates as set forth herein. Accordingly, such engineered conjugates are expressly contemplated as being within the scope of the present disclosure. In other embodiments, the disclosed anti-cancer agents will be given in combination with site-specific conjugates comprising a different therapeutic agent as set forth above.
  • an effective amount of (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor to treat cancer harboring a KRAS G12C mutation (i.e., a cancer comprising one or more cancer cells that express a KRAS G12C mutant protein) in a subject, comprising administering to the subject an effective amount of (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor.
  • the ERK1/2 inhibitor is used for the manufacture of a medicament for treating cancer, wherein the treatment is in combination with a KRAS G12C inhibitor.
  • the ERK1/2 inhibitor and the KRAS G12C inhibitor are used for the manufacture of a medicament for treating cancer, wherein the treatment is in combination with a KRAS G12C inhibitor.
  • the cancer is lung cancer.
  • the cancer is colorectal cancer.
  • the cancer is pancreatic cancer.
  • any of the methods as described herein for the treatment of a cancer harboring a KRAS G12C mutation i.e., a cancer comprising one or more cancer cells that express a KRAS G12C mutant protein
  • a cancer harboring a KRAS G12C mutation i.e., a cancer comprising one or more cancer cells that express a KRAS G12C mutant protein
  • administering comprising administering to the subject an effective amount of (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor.
  • ERK1/2 and ERK1/2 inhibitors ERK1/2 and ERK1/2 inhibitors.
  • the methods and uses of the present disclosure may be combined with an additional therapeutic agent, such as an anti-cancer agent, including an anti-cancer small molecule inhibitor.
  • the additional therapeutic agent may also be an antagonist or an inhibitor of a kinase.
  • the kinase is involved in the RAS/RAF/MEK/ERK pathway.
  • the kinase is an extracellular signal-regulated kinase (ERK) .
  • the ERK is ERK1.
  • the ERK kinase is ERK2 (also known as MAPK1) .
  • the ERK kinases are terminal kinases of phosphorelay signaling pathways that govern growth and mitogenic signals.
  • the ERK kinases phosphorylate substrates that are involved in regulating cell proliferation, survival, growth, metabolism, migration and differentiation.
  • the treatment results in a tumor growth inhibitor of at least more than about 70%, 75%, 80%, 85%, 90%, 95%or 97%. In some embodiments, the treatment results in a tumor regression. In some embodiments, the treatment results in a prolonged or sustainable tumor inhibition, regression or eradiation effect for more than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, or 140 days as compared to a monotherapy of a G12C inhibitor or a monotherapy of an ERK 1/2 inhibitor. In some embodiments, the treatment results in a sustainable tumor inhibition, regression or eradiation effect for more than 5, 10, 15, 20, 25, or 30 days after the treatment is stopped.
  • the present application also provides use of any of the ERK1/2 inhibitors described herein for treating a cancer with a BRAF aberration (e.g., V600E) or a KRAS aberration (e.g., any of the mutant KRAS described in the “mutant KRAS” section, e.g., KRAS G12C, e.g., KRAS G12D) .
  • a BRAF aberration e.g., V600E
  • a KRAS aberration e.g., any of the mutant KRAS described in the “mutant KRAS” section, e.g., KRAS G12C, e.g., KRAS G12D
  • the ERK 1/2 inhibitor comprises an agent comprising a formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n is 0 or 1;
  • m is 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R d ;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • the present application also provides use of any of the G12C inhibitors described herein for treating a cancer with KRAS G12C mutation in combination with an EGFR inhibitor (e.g., an anti-EGFR antibody, e.g., cetuximab) .
  • an EGFR inhibitor e.g., an anti-EGFR antibody, e.g., cetuximab
  • the cancer is a pancreatic cancer, a lung cancer or a colorectal cancer.
  • the KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from O and N; R1 is selected from C6-10 aryl and 5-to 10-membered heteroaryl, wherein the C 6-10 aryl and 5-to 10-membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 R a ; when T 1 is O, R 2 is not present; when T 1 is N, R 2 is selected from H, C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1-3 alkyl, wherein the C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1-3 alkyl are optionally substituted with 1, 2 or 3 R b ; R 3 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ; R 4 is selected from H and C 1-3 alkyl, wherein the C 1- 3 alkyl is optionally substitute
  • the present application also provides a composition (e.g., a pharmaceutical composition) comprising both a KRAS G12C inhibitor (e.g., Compound 17) and a ERK 1/2 inhibitor (e.g., WX001) .
  • the composition further comprises a pharmaceutical carrier.
  • Kirsten rat sarcoma (KRAS) gene belongs to a member of the RAS family and its mutations are genetic drivers of multiple cancer types, especially colorectal cancer (CRC) , pancreatic ductal adenocarcinoma (PDAC) , and non-small cell lung cancer (NSCLC) .
  • KRAS-G12 mutations (89%) predominate in human cancers, followed by G13 (9%) and Q61 (1%) mutations.
  • the G12D mutation is the most common mutation among three common G12C (14%) , G12D (36%) , and G12V (23%) mutations.
  • G12C is the most common mutation subtype in NSCLC (13%) .
  • Identifying specific types of KRAS mutations in combination with other gene mutations may provide information about disease aggressiveness or drug sensitivity, which is the basis of precision medicine or personalized care. See e.g., Liu et al., Cancer Gene Ther 29, 875–878 (2022) .
  • KRAS protein is a signaling GTPase that switches between the active GTP-bound and inactive GDP-bound conformations.
  • Guanine nucleotide exchange factors GEF
  • GAP GTPase-activating proteins
  • RTKs receptor tyrosine kinases
  • SOS1 SOS Ras/Rac guanine nucleotide exchange factor 1
  • PTPN11 protein tyrosine phosphatase non-receptor type 11
  • SOS1 SOS Ras/Rac guanine nucleotide exchange factor 1
  • PTPN11 protein tyrosine phosphatase non-receptor type 11
  • SHP2 protein tyrosine phosphatase non-receptor type 11
  • the mutant cysteine 12 is located next to the pocket (P2) in the switch-II region.
  • the KRAS mutation disrupts the guanine exchange cycle, thereby locking it in an inactive GDP-bound form that drives pro-tumorigenic signals.
  • the oncogenic KRAS signal establishes the main signal axis of tumor cell proliferation and survival, providing a key target for cancer treatment. See e.g., Liu et al., Cancer Gene Ther 29, 875–878 (2022) .
  • KRAS-G12C inhibitors sotorasib and adagrasib are used to treat patients with advanced non-small cell lung cancer (NSCLC) carrying KRAS-G12C mutations.
  • NSCLC non-small cell lung cancer
  • KRAS-G12C inhibitors sotorasib and adagrasib are used to treat patients with advanced non-small cell lung cancer (NSCLC) carrying KRAS-G12C mutations.
  • NSCLC non-small cell lung cancer
  • KRAS-G12C inhibitor therapy mainly due to intrinsic or acquired resistance caused by cellular, molecular, and genetic mechanisms. Improving the understanding of drug response in the tumor microenvironment may continue to promote the design, testing, and clinical application of KRAS-G12C inhibitors. See e.g., Liu et al., Cancer Gene Ther 29, 875–878 (2022) .
  • the KRAS inhibitor is an inhibitor that inhibits the G12C variant of KRAS (i.e., KRAS G12C) .
  • KRAS G12C inhibitor refers to any agent, e.g., polypeptide, fusion polypeptide, antibody, peptide, antisense oligonucleotide, or small molecule drug, that inhibits the activity of the KRAS G12C mutant protein.
  • the KRAS G12C inhibitor interacts directly with the KRAS G12C mutant protein to inhibit the protein’s activity.
  • the KRAS G12C inhibitor is a small molecule drug. In some embodiments, the KRAS G12C inhibitor is a small molecule (e.g., an irreversible small molecule inhibitor) that inhibit KRAS activity by forming irreversible covalent bonds with cysteine residues of KRAS G12C mutant protein.
  • a small molecule e.g., an irreversible small molecule inhibitor
  • Exemplary KRAS G12C inhibitors include, but are not limited to a class of KRAS G12C inhibitors.
  • the molecular mode of action (MOA) of this class of KRAS G12C inhibitors is allosteric binding to the Switch II pocket of the GDP-bound form of the KRAS G12C protein and forming a covalent bond at the cysteine-12 position. This irreversible conjugation traps KRASG12C in its GDP-bound inactive state.
  • This class of KRAS G12C inhibitors with the same mechanism of action (MOA) includes sotorasib, adgrasib, JDQ443, GDC-6036, etc.
  • ERK1/2 inhibitor e.g., WX001
  • the exemplary KRAS G12C inhibitor is predicted to extend to all KRAS G12C inhibitors of the same class.
  • the KRAS G12C inhibitor comprises or is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from O and N;
  • R 1 is selected from C6-10 aryl and 5-to 10-membered heteroaryl, wherein the C6-10 aryl and 5-to 10-membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 Ra;
  • R 3 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 4 is selected from H and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
  • R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 F;
  • R 8 is selected from H and CH 3 ;
  • R a is each independently selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl and C 2-3 alkenyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl and C 2-3 alkenyl are optionally substituted with 1, 2 or 3 F;
  • R b is each independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R c is each independently selected from 4- to 8-membered heterocycloalkyl, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
  • R d is each independently selected from F, Cl, Br, I, OH, NH 2 and CN;
  • R is each independently selected from H, F, Cl, Br, OH, CN, C 1-3 alkyl, C 1-3 alkoxy and -C 1-3 alkyl-O-CO-C1-3 alkylamino;
  • R 1 is naphthyl
  • the naphthyl is optionally substituted with F, Cl, Br, OH, NH 2 , CF 3 , CH 2 CH 3 and -C ⁇ CH
  • R 5 , R 6 and R 7 are each independently H.
  • the above Ra is each independently selected from F, OH, NH 2 , CH 3 , CF 3 , CH 2 CH 3 and -C ⁇ CH, and other variables are as defined in this disclosure.
  • R 1 is selected from phenyl, naphthyl, indolyl and indazolyl, wherein the phenyl, naphthyl, indolyl and indazolyl are optionally substituted with 1, 2 or 3 R a , and other variables are as defined in this disclosure.
  • R 1 is selected from and other variables are as defined in this disclosure.
  • R 2 is selected from H, CH 3 , CH 2 CH 3 and CH (CH 3 ) 2 , wherein the CH3, CH2CH3 and CH (CH3) 2 are optionally substituted with 1, 2 or 3 R b , and other variables are as defined in this disclosure.
  • R 2 is selected from H and CH3, and other variables are as defined in this disclosure.
  • the above R is each independently selected from H, F, Cl, Br, OH, CN, CH 3 , CH 2 CH 3 , CH 2 CF 3 , OCH 3 , OCF 3 and and other variables are as defined in this disclosure.
  • the above R c is selected from tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl, wherein the tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl are optionally substituted with 1, 2 or 3 R, and other variables are as defined in this disclosure.
  • R c is selected from and other variables are as defined in this disclosure.
  • R c is selected from and other variables are as defined in this disclosure.
  • R 3 is CH 3 , wherein the CH 3 is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in this disclosure.
  • R 3 is selected from and other variables are as defined in this disclosure.
  • R 3 is selected from and other variables are as defined in this disclosure.
  • R 4 is selected from H and CH 3 , wherein the CH 3 is optionally substituted with 1, 2 or 3 R d , and other variables are as defined in this disclosure.
  • R 4 is selected from H, CH 3 and CH 2 CN, and other variables are as defined in this disclosure.
  • the present disclosure provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • T1 is selected from O and N;
  • R1 is selected from phenyl, naphthyl and indazolyl, wherein the phenyl, naphthyl and indazolyl are optionally substituted with 1, 2, 3, 4 or 5 R a ;
  • R 3 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 4 is selected from H and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
  • R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R 8 is selected from H and CH 3 ;
  • R a is each independently selected from F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CF 3 and OCH 3 ;
  • R b is each independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R c is each independently selected from tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl, wherein the tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl are substituted with 1, 2 or 3 R;
  • R d is each independently selected from F, Cl, Br, I, OH, NH 2 and CN;
  • R is each independently selected from H, F, Cl, Br and CH 3 .
  • R 4 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
  • T 1 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and R d are as defined in this disclosure;
  • the carbon atom with “*” is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or is enriched in one enantiomer.
  • R 1 is selected from phenyl, naphthyl and wherein the phenyl, naphthyl and are optionally substituted with 1, 2 or 3 R a , and other variables are as defined in this disclosure.
  • R 1 is selected from and other variables are as defined in this disclosure.
  • R 2 is selected from H, CH 3 , CH 2 CH 3 and CH (CH 3 ) 2 , wherein the CH 3 , CH 2 CH 3 and CH (CH 3 ) 2 are optionally substituted with 1, 2 or 3 R b , and other variables are as defined in this disclosure.
  • R 2 is selected from H and CH 3 , and other variables are as defined in this disclosure.
  • R c is selected from and other variables are as defined in this disclosure.
  • R c is selected from and other variables are as defined in this disclosure.
  • R 3 is CH 3 , wherein the CH 3 is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in this disclosure.
  • R 3 is selected from and other variables are as defined in this disclosure.
  • R 3 is selected from and other variables are as defined in this disclosure.
  • R 4 is selected from H and CH3, wherein the CH 3 is optionally substituted with 1, 2 or 3 R d , and other variables are as defined in this disclosure.
  • R 4 is selected from H, CH 3 and CH 2 CN, and other variables are as defined in this disclosure.
  • the present disclosure provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from O and N;
  • R 1 is selected from phenyl, naphthyl and indazolyl, wherein the phenyl, naphthyl and indazolyl are optionally substituted with 1, 2, 3, 4 or 5 R a ;
  • R 3 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 4 is selected from H and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
  • R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R 8 is selected from H and CH 3 ;
  • R a is each independently selected from F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CF 3 and OCH 3 ;
  • R b is each independently selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • R c is each independently tetrahydropyrrolyl, wherein the tetrahydropyrrolyl is substituted with 1, 2 or 3 R;
  • R d is each independently selected from F, Cl, Br, I, OH, NH 2 and CN;
  • R is each independently selected from F, Cl, Br and CH 3 .
  • T 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in this disclosure; the carbon atom with “*” is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or is enriched in one enantiomer.
  • R 1 is selected from phenyl, naphthyl and wherein the phenyl, naphthyl and are optionally substituted with 1, 2 or 3 R a , and other variables are as defined in this disclosure.
  • R 1 is selected from and other variables are as defined in this disclosure.
  • R 2 is selected from H, CH 3 , CH 2 CH 3 and CH (CH 3 ) 2 , wherein the CH 3 , CH 2 CH 3 and CH (CH 3 ) 2 are optionally substituted with 1, 2 or 3 R b , and other variables are as defined in this disclosure.
  • R 2 is selected from H and CH3, and other variables are as defined in this disclosure.
  • R c is and other variables are as defined in this disclosure.
  • R 3 is CH 3 , wherein the CH 3 is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in this disclosure.
  • R 4 is CH 3 , wherein the CH 3 is optionally substituted with 1, 2 or 3 R d , and other variables are as defined in this disclosure.
  • R 4 is CH 2 CN, and other variables are as defined in this disclosure.
  • the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from O and N;
  • R 1 is selected from phenyl and naphthyl, wherein the phenyl and naphthyl are optionally substituted with 1, 2 or 3 R a ;
  • R 3 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R4 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
  • R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R a is each independently selected from F, Cl, Br, I, OH, NH 2 , CN, CH 3 and OCH 3 ;
  • R b is each independently selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • R c is each independently tetrahydropyrrolyl, wherein the tetrahydropyrrolyl is substituted with 1, 2 or 3 R;
  • R d is each independently selected from F, Cl, Br, I, OH, NH 2 and CN;
  • R is each independently selected from F, Cl, Br and CH 3 ; the carbon atom with “*” is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or is enriched in one enantiomer.
  • R 1 is naphthyl, wherein the naphthyl is optionally substituted with 1, 2 or 3 R a , and other variables are as defined in this disclosure.
  • R 1 is selected from and other variables are as defined in this disclosure.
  • R 2 is selected from CH 3 , CH 2 CH 3 and CH (CH 3 ) 2 , wherein the CH 3 , CH 2 CH 3 and CH (CH 3 ) 2 are optionally substituted with 1, 2 or 3 Rb, and other variables are as defined in this disclosure.
  • R 2 is CH 3 , and other variables are as defined in this disclosure.
  • R c is and other variables are as defined in this disclosure.
  • R 3 is CH 3 , wherein the CH 3 is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in this disclosure.
  • R 4 is CH 3 , wherein the CH 3 is optionally substituted with 1, 2 or 3 R d , and other variables are as defined in this disclosure.
  • R 4 is CH 2 CN, and other variables are as defined in this disclosure.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from phenyl and naphthyl, wherein the phenyl and naphthyl are optionally substituted with 1, 2 or 3 R a ;
  • R 3 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 4 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
  • R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R a and R b are each independently selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • Rc is each independently tetrahydropyrrolyl, wherein the tetrahydropyrrolyl is substituted with 1, 2 or 3 R;
  • R d is each independently selected from F, Cl, Br, I, OH, NH 2 and CN;
  • R is each independently selected from F, Cl, Br and CH 3 ;
  • the carbon atom with “*” is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or is enriched in one enantiomer.
  • R 1 is naphthyl, and other variables are as defined in this disclosure.
  • R 1 is and other variables are as defined in this disclosure.
  • R 2 is selected from CH3, CH 2 CH 3 and CH (CH 3 ) 2 , wherein the CH 3 , CH 2 CH 3 and CH (CH 3 ) 2 are optionally substituted with 1, 2 or 3 Rb, and other variables are as defined in this disclosure.
  • R 2 is CH 3 , and other variables are as defined in this disclosure.
  • R c is and other variables are as defined in this disclosure.
  • R 3 is CH 3 , wherein the CH 3 is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in this disclosure.
  • R 4 is CH 3 , wherein the CH 3 is optionally substituted with 1, 2 or 3 R d , and other variables are as defined in this disclosure.
  • R 4 is CH 2 CN, and other variables are as defined in this disclosure.
  • R 1 , R 5 , and R c are as defined in this disclosure
  • R 4 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
  • R d is each independently selected from F, Cl, Br, I, OH, NH 2 and CN;
  • the carbon atom with “*” is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or is enriched in one enantiomer.
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R are as defined in this disclosure.
  • the present disclosure also includes some embodiments obtained by any combination of the above variables.
  • the present disclosure provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the KRAS G12C compound is Compound 17 with the structure below, or a pharmaceutically acceptable salt thereof.
  • the compounds discussed above have good cell proliferation inhibitory activity on KRASG12C-mutated MIA-PA-CA-2 cell line and NCI-H358 cells.
  • the compounds of the present disclosure have good stability in liver microsomes, hepatocytes, plasma and whole blood, as well as good PK properties and significant anti-tumor effect. See e.g., US20230151004A1 and WO2023/036282 which are incorporated herein by reference by their entirety.
  • the manufacture and/or synthesis of the compounds discussed above can be found in US20230151004A1 and/or WO2023/036282.
  • Exemplary KRAS G12C inhibitors that find use with the methods provided herein include, without limitation, e.g., sotorasib, adagrasib, JAB-21822, GDC-6036, JDQ443, D-1553, GH35, GFH925, BPI-421286, and LY3537982, RMC-6291, RMC-8839, HBI-2438, Compound 17, and JNJ-74699157, BI 1823911, MK-1084, HS-10370, JMKX001899, YL-15293, ZG19018, XNW14010, HJ891, BEBT-607, GEC-255, and JS116.
  • KRAS G12C inhibitors are described in, e.g., Hillig et al. (2019) Proc Natl Acad Sci U S A. 116 (7) : 2551–2560 and Sun et al. (2012) Angew Chem Int Ed Engl.
  • the KRAS G12C inhibitor is AMG 510, which, as noted above, is also known as sotorasib, LUMAKRAS TM , and LUMYKRAS TM .
  • AMG 510 is currently under development by Amgen/Beigene.
  • AMG 510 can exist in either of two atropisomeric forms and one is more active than the other (see, e.g., https: //cen (dot) acs (dot) org/pharmaceuticals/drug (dash) discovery/Amgen (dash) unveils (dash) KRas (d ash) inhibitor (dash) human/97/i14) .
  • AMG 510 selectively forms an irreversible covalent bond to the sulfur atom in the cysteine residue that is present in the G12C mutated form of the KRAS protein, but not in the wild type form.
  • the covalent binding of AMG 150 to KRAS G12C locks the protein in its inactive GDP-bound conformation, thus inhibiting KRAS-dependent signal transduction.
  • AMG 150 has the empirical formula C30HF2N6O3 and a molecular weight of 560.606 g/mol.
  • AMG 150 is described chemically as 6-Fluoro-7- (2-fluoro-6-hydroxyphenyl) - (1M) -1- [4-m90cFv90ine- (propan-2-yl) pyridin-3-yl] -4- [ (2S) -2-methyl-4- (prop-2-enoyl) piperazin-1-yl] pyrido [2, 3-d] pyrimidin-2 (1H) -one and has the following chemical structure:
  • the CAS Registry Number for AMG 510 is 2252403-56-6.
  • the efficacy of AMG 510 was demonstrated in a subset of patients enrolled in a single-arm, open-label, multicenter trial (NCT03600883) and is currently being investigated in further clinical trials.
  • Complete information about AMG 510 preparation, dispensing, dosage, and administration schedule can be found in the local package insert (for the United States, see, e.g.., www (dot) accessdata (dot) fda (dot) gov/drugsatfda_docs/label/2021/214665s000lbl. pdf. Further details regarding the structure and synthesis of AMG 510 are provided in WO 2018/217651, the contents of which are incorporated herein by reference in their entirety.
  • the KRAS G12C inhibitor is MRTX849 (also known as adagrasib) .
  • MRTX849 which is currently under development by Mirati/Zai Lab.
  • AMG 510 MRTX849 selectively forms an irreversible covalent bond to the sulfur atom in the cysteine residue that is present in the G12C mutated form of the KRAS protein, but not in the wild type form.
  • the covalent binding of MRTX849 to KRAS G12C locks the protein in its inactive GDP-bound conformation, thus inhibiting KRAS-dependent signal transduction.
  • MRTX849 has the empirical formula C 32 H 35 ClFN 7 O 2 and a molecular weight of 604.13 g/mol. MRTX849 is described chemically as 2- [ (2S) -4- [7- (8-chloronaphthalen-1-yl) -2- [ [ (2S) -1-methylpyrrolidin-2-yl] methoxy] -6, 8-dihydro-5H-pyrido [3, 4-d] pyrimidin-4-yl] -1- (2-fluoroprop-2-enoyl) piperazin-2-yl] acetonitrileand has the following chemical structure:
  • MRTX849 The CAS Registry Number for MRTX849 is 2326521-71-3. MRTX849 is currently being evaluated in several clinical trials, including NCT04613596, NCT04685135, NCT03785249, NCT04330664, and others. Further details regarding the structure and synthesis of MRTX849 are provided in Fell et al. (2020) J. Med. Chem. 63, 6679-6693 and WO 2017/201161, the contents of which are incorporated herein by reference in their entirety.
  • the KRAS G12C inhibitor is JAB-21822.
  • JAB-21822 is currently being evaluated in several clinical trials, including NCT05009329 and NCT05002270. Further details regarding the structure and synthesis of JAB-21822 are provided in WO 2021/057832, the contents of which are incorporated herein by reference in their entirety.
  • the KRAS G12C inhibitor is GDC-6036.
  • GDC-6036 is being developed by Genentech, Inc. (see, e.g., www (dot) genentechoncology (dot) com/pipeline-molecules/kras-g12c. html) and is currently being evaluated clinical trial NCT04449874. Further details regarding the structure and synthesis of GDC-6036 are provided in WO 2020/097537, the contents of which are incorporated herein by reference in their entirety.
  • the KRAS G12C inhibitor is JDQ443.
  • JDQ443 is an inhibitor of KRAS G12C that is being developed by Novartis.
  • the structure of JDQ443 is:
  • JDQ443 is currently being evaluated in clinical trial NCT04699188. Further details regarding the synthesis of JDQ443 are provided in WO 2021/124222, the contents of which are incorporated herein by reference in their entirety.
  • the KRAS G12C inhibitor is D-1553.
  • D-1553 is being developed by InventisBio Co., Ltd. (see, e.g., www (dot) inventisbio (dot) com/%e4%b8%b4%e5%ba%8a%e8%af%95%e9%aa%8c/) and is currently being evaluated in clinical trial NCT04585035 in collaboration with Merck Sharp & Dohme. Further details regarding the structure and synthesis of D-1553 are provided in WO 2020/233592, the contents of which are incorporated herein by reference in their entirety.
  • the KRAS G12C inhibitor is GH35.
  • GH35 is being developed by Suzhou Genhouse Bio Co., Ltd. (see, e.g., www (dot) genhousebio (dot) com/en/product/index (dot) html) and is being evaluated in clinical trial NCT05010694. Further details regarding the structure and synthesis of GH35 are provided in WO2020/177653, the contents of which are incorporated herein by reference in their entirety.
  • the KRAS G12C inhibitor is GFH925.
  • GFH925 is being developed by GenFleet Therapeutics (Zhejiang) (see, e.g., www (dot) genfleet (dot) com/en/science) and is being evaluated in clinical trial NCT05005234. Further details regarding the structure and synthesis of GFH925 are provided in WO 2020/177629, WO 2020/221239, and WO 2021/031952, the contents of which are incorporated herein by reference in their entirety.
  • the KRAS G12C inhibitor is BPI-421286.
  • BPI-421286 is being developed by Betta Pharmaceutical Co., Ltd (see, e.g., www (dot) bettapharma (dot) com/News/show/id/2380) , and clinical trial applications for the evaluation of BPI-421286 (CXHL2100046 and CXHL2100047) have been accepted by the State Food and Drug Administration of the People’s Republic of China. Further details regarding the structure and synthesis of BPI-421286 are provided in CN112390796, the contents of which are incorporated herein by reference in their entirety.
  • the KRAS G12C inhibitor is LY3537982.
  • LY3537982 is being developed by Eli Lilly and Company and Loxo Oncology, Inc. (see, e.g., www (dot) lillyloxooncologypipeline (dot) com/molecule/kras-g12c-inhibitor/) , and is being investigated in clinical trial NCT04956640. Further details regarding the structure and synthesis of LY3537982 are provided in WO2021/118877, the contents of which are incorporated herein by reference in their entirety.
  • the KRAS G12C inhibitor is RMC-6291.
  • RMC-6291 is being developed Revolution Medicines.
  • the KRAS G12C inhibitor is RMC-8839.
  • RMC-8839 is being developed by Revolution Medicines.
  • the KRAS G12C inhibitor is HBI-2438.
  • HBI-2438 is being developed by Huya Bioscience and Jemin Biocare, and is being investigated in clinical trial NCT05485974.
  • the KRAS G12C inhibitor is JNJ-74699157 (ARS-3248) .
  • JNJ-74699157 is being developed by Johnson and Johnson and Wellspring Biosciences, and was investigated in clinical trial NCT04006301.
  • Extracellular Regulated Protein kinase (ERK) 1 and ERK2 are the main players and the terminal signaling kinases involved in the Ras/Raf/MEK/ERK pathway.
  • ERK1/2 act as key signaling nodules downstream of the Ras-Raf-MEK-ERK pathway and has been shown to be overly activated in human cancers driven by RAS or RAF mutations. Innate resistance to RAF or MEK inhibitors is, in part, due to loss of regulation via a negative feedback loop and pathway re-activation.
  • ERK 1/2 are directly phosphorylated by MEK 1 and MEK 2.
  • Phosphoylated (e.g., activated) ERK1/2 kinases subsequently phosphorylate numerous substrates which regulate cell cycle progression, differentiation, and survival (Sugiura et al., Cells, 10 (10) : 2509 (2021) ) .
  • ERK 1/2 regulated transcription factors control genes that play significant roles in critical cellular processes such as cellular proliferation and cell cycle progression.
  • ERK 1/2 mediated phosphorylation of certain protein substrates such as focal adhesion kinase promotes cancer cell migration.
  • ERK 1/2 inhibitors are known to inhibit the ERK kinases through one of two major mechanisms. ERK inhibitors can inhibit ERK catalytic activity through competition for the ATP binding site.
  • the ERK1/2 inhibitor is an inhibitor that inhibits ERK1/2.
  • the term “ERK1/2” refers to any agent, e.g., polypeptide, fusion polypeptide, antibody, peptide, antisense oligonucleotide, or small molecule drug, that inhibits the activity of the ERK 1/2 proteins (e.g., the ERK 1/2 kinases) .
  • the ERK1/2 inhibitor interacts directly with the ERK1/2 protein to inhibit the protein’s activity.
  • the ERK1/2 inhibitor is a small molecule drug.
  • the ERK1/2 inhibitor is a small molecule (e.g., a reversible, small molecule catalytic ERK1/2 inhibitor) that inhibits ERK1/2 catalytic activity by competing with ATP for binding to the ERK1/2 protein.
  • the ERK1/2 inhibitor is a small molecule (e.g., a dual mechanism ERK1/2 inhibitor) that inhibits ERK1/2 activity preventing the formation of the active conformation of ERK1/2.
  • the ERK1/2 inhibitor prevents phosphorylation of ERK 1/2.
  • the ERK1/2 inhibitor is a thiazolactam spiroheterocyclic compound, such as the ERK1/2 inhibitor disclosed in WO2023274256, which is herein incorporated by reference.
  • the manufacture and/or synthesis of the ERK1/2 inhibitor can be found in WO2023274256.
  • the ERK1/2 inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n 0 or 1
  • n 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • R 1 and R 2 are independently selected from H, CH 3 and CH 2 CH 3 , and said CH 3 and CH 2 CH 3 are either is optionally substituted by 1, 2 or 3 R a .
  • R 1 and R 2 are independently selected from H, CH 3 , CHF 2 , CD 3 and CH 2 CH 3 .
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and CH 3 , and the CH3 is optionally substituted by 1, 2 or 3 R c .
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and CH 3 .
  • R is selected from F, Cl, Br, I, CH 3 and OCH 3 , and the CH 3 and OCH 3 are optionally replaced by 1, 2 or 3 R substitutions.
  • the R d is selected from CH 3 and OCH 3 .
  • the ring A is selected from the group consisting of and the are optionally substituted by 1, 2 or 3 R d .
  • the Ring A is selected from the group consisting of
  • the structural unit is
  • the compound or pharmaceutically acceptable salt thereof is selected from
  • R 2 is as defined in any one of claims 1 to 3;
  • R 6 and R 7 are as defined in any one of claims 1, 4 or 5.
  • the ERK1/2 inhibitor comprises an agent comprising WX001 with the following formula or pharmaceutically acceptable salt thereof,
  • the compound is Form A of WX001, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 10.2080 ⁇ 0.2000°, 18.8429 ⁇ 0.2000°, 20.6217 ⁇ 0.2000°;
  • the ERK1/2 inhibitor has a X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 10.2080 ⁇ 0.2000°, 18.8429 ⁇ 0.2000°, 20.6217 ⁇ 0.2000°, 25.0767 ⁇ 0.2000°, 25.4797 ⁇ 0.2000°.
  • the ERK1/2 inhibitor has a X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 ⁇ angles: 10.2080 ⁇ 0.2000°, 15.2687 ⁇ 0.2000°, 17.6747 ⁇ 0.2000°, 18.8429 ⁇ 0.2000°, 20.6217 ⁇ 0.2000°, 21.0531 ⁇ 0.2000°, 25.0767 ⁇ 0.2000°, 25.4797 ⁇ 0.2000°.
  • the ERK1/2 inhibitor has a X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2 ⁇ angles: 10.2080 ⁇ 0.2000°, 14.4684 ⁇ 0.2000°, 15.2687 ⁇ 0.2000°, 17.6747 ⁇ 0.2000°, 18.8429 ⁇ 0.2000 °, 20.6217 ⁇ 0.2000 °, 21.0531 ⁇ 0.2000 °, 21.5713 ⁇ 0.2000 °, 22.0420 ⁇ 0.2000 °, 22.4540 ⁇ 0.2000 °, 25.0767 ⁇ 0.2000 °, 25.4797 ⁇ 0.2 0.2 000 °.
  • the ERK1/2 inhibitor has a X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 10.2080°, 10.4856°, 14.4684°, 15.0133°, 15.2687°, 15.9518°, 16.6214°, 17.6747°, 17.9514°, 18.4703°, 18.8429°, 19.1531°, 20.6217°, 21.0531°, 21.2894°, 21.5713°, 22.0420°, 22.4540°, 25.0767°, 25.4797°, 26.3 255°, 26.9544°.
  • the ERK1/2 inhibitor has a differential scanning calorimetry curve that has an endothermic starting point at 241.0 ⁇ 3.0°C.
  • the ERK1/2 inhibitor has a thermogravimetric analysis curve that has a weight loss of 0.83%at 150.0 ⁇ 3.0°C.
  • Exemplary small molecule ERK 1/2 inhibitors that find use with the methods provided herein include, without limitation, e.g., BVD-523 (ulixertinib) , CC-90003, GDC-0994 (Ravoxertinib) , KO-947, LTT462, LY3214996 (temuterkib) , SCH772984, ERA007, ASN007, FR180204, and MK-8353.
  • the ERK 1/2 inhibitor is BVD-523, which is also known as ulixertinib and VRT752271.
  • BVD-523 is currently under development by BioMed Valley.
  • BVD-523 is a reversible, ATP-competitive oral inhibitor.
  • BVD-523 has an empirical formula of empirical formula C21H22Cl2N4O2 and a molecular weight of 433.33 g/mol.
  • BVD-523 is described chemically as (S) -4- (5-chloro-2- (isopropylamino) pyridin-4-yl) -N- (1- (3-chlorophenyl) -2-hydroxyethyl) -1H-pyrrole-2-carboxamide hydrochloride and has the following chemical structure:
  • BVD-523 The CAS Registry Number for BVD-523 is 869886-67-9.
  • the efficacy of BVD-523 was demonstrated in a subset of patients enrolled in a multicenter, dose escalation trial (NCT01781429) and is currently being investigated in further clinical trials.
  • the ERK 1/2 inhibitor is CC-90003.
  • CC-90003 is a covalent inhibitor of ERK 1/2 that was developed by Celgene.
  • the ERK 1/2 inhibitor is GDC-0994, which is also known as ravoxertinib.
  • GDC-0994 was developed by Array and Genentech.
  • GDC-0994 has a CAS number of 1453848-26-4, and is also known as 1- [ (1S) -1- (4-chloro-3-fluorophenyl) -2-hydroxyethyl] -4- [2- [ (2-methylpyrazol-3-yl) amino] pyrimidin-4-yl] pyridin-2-one.
  • the molecular formula is C21H18ClFN6O2 and has a molecular weight of 440.863 g/mol.
  • GDC-0994 Efficacy of GDC-0994 was demonstrated in a subset of patients enrolled in an open label, multicenter, dose escalation trial (NCT01875705) . Further details regarding the structure and synthesis of GDC-0994 is provided in WO2013/130976, the contents of which are incorporated herein by reference in their entirety.
  • the ERK 1/2 inhibitor is KO-947 developed by Araxes Pharma and Kura Oncology. Further details regarding the structure and synthesis of KO-947 is provided in WO2015/051341, the contents of which are incorporated herein by reference in their entirety.
  • the ERK 1/2 inhibitor is LTT462, which is also known as rineterkib and was developed by Novartis.
  • LTT462 has a chemical formula of C 26 H 27 BrF 3 N 5 O 2 .
  • the ERK 1/2 inhibitor is LY3214996, which is also known as temuterkib.
  • LY3214996 is being developed by Eli Lilly. The efficacy of temuterkib is currently being investigated in clinical trials.
  • the ERK 1/2 inhibitor is SCH772984.
  • SCH772984 is under development by Merck.
  • SCH772984 has a CAS number of 942183-80-4, a molecular formula of C 33 H 33 N 9 O 2 , and a molecular weight of 587.67 g/mol.
  • the ERK 1/2 inhibitor is FR180204.
  • FR180204 is also known as 5- (2-phenylpyrazolo [1, 5-a] pyridin-3-yl) -1H-pyrazolo [3, 4-c] pyridazin-3-amine.
  • the CAS number is 865362-74-9, has a molecular formula of C18H13N7, and a molecular weight of 327.3 g/mol.
  • the ERK 1/2 inhibitor is MK-8353 (SCH 900353) .
  • MK-8353 is under development by Merck.
  • MK-8353 has a CAS number of 1184173-73-6, a molecular weight of 691.84 g/mol, and has the formula C37H41N9O3S.
  • the cancer is resistant to a prior KRAS treatment (e.g., a treatment involves a KRAS-G12C inhibitor, e.g., cancer has acquired resistance to a KRAS G12C inhibition, e.g., cancer being resistant or acquired resistant to a KRAS inhibitor such as MRTX849, AMG510, or Compound 17) . ) .
  • the cancer e.g., cancer cells
  • the partial response is determined by the absence of tumor regression.
  • the partial response is determined by no more than about 90%, 80%, 70%, 60%, 50%, 40%, 30%, or 20%of tumor growth inhibition (e.g., as calculated by methods described herein) .
  • KRAS-G12C inhibitors namely sotorasib (also known as AMG 510 or Lumakras) and adagrasib (also known as MRTX849) , which act by selectively forming a covalent bond with cysteine 12 within the switch-II pocket of KRAS-G12C protein, thereby locking KRAS in the inactive state to arrest cell proliferation.
  • sotorasib also known as AMG 510 or Lumakras
  • adagrasib also known as MRTX849
  • sotorasib and adagrasib selectively impair the viability of KRAS-G12C mutant cell lines, but do not affect cell lines with other KRAS mutations in vitro and in vivo. Both sotorasib and adagrasib have long half-life (5.5–24h) and extensive tissue distribution in human. Unexpectedly, neither sotorasib nor adagrasib affects PI3K signaling, indicating that the upstream pathway independent of KRAS-G12C facilitates the activation of PI3K, which provides an explanation for the formation of KRAS-G12C inhibitor resistance.
  • KRAS-G12C inhibitor treatment Emerging preclinical and clinical evidence shows that the biggest obstacle to KRAS-G12C inhibitor treatment is the inevitable emergence of drug resistance. Although the problem of resistance to therapy is multifaceted, intercellular variability or intratumoral heterogeneity is considered to be the main factor leading to KRAS-G12C inhibitor resistance.
  • Single-cell RNA sequencing analysis of KRAS-G12C mutant NSCLC cell line treated with KRAS-G12C inhibitor ARS1620 demonstrated that the subpopulation of cells synthesizing the new KRAS-G12C protein, rather than the wild-type KRAS protein, is the cause of adaptive resistance. See e.g., Nature. 2020 Jan; 577 (7790) : 421-425.
  • NCT04330664 Clinical trials (NCT04330664) are ongoing to test the combination with TNO155 (SHP2 inhibitor) and adagrasib in patients with advanced solid tumors carrying KRAS-G12C mutation.
  • TNO155 SHP2 inhibitor
  • adagrasib adagrasib in patients with advanced solid tumors carrying KRAS-G12C mutation.
  • the activation of the PI3K-AKT-mTOR pathway contributes to the development of sotorasib resistance in human PDAC cell line in vitro and in xenograft mouse models.
  • Gene set enrichment analysis and mass spectrometry-based phosphoproteomics analysis found that induction of epithelial-to-mesenchymal transition (EMT) promotes resistance to sotorasib or ARS-1620 through activation of PI3K or ERK pathway in NSCLC cells in a cell type-dependent manner.
  • EMT epithelial-to-mesenchymal transition
  • Nuclear factor, erythroid 2 like 2 (NFE2L2, best known as NRF2) regulated by kelch like ECH associated protein 1 (KEAP1) is a key transcription factor in cellular antioxidant response.
  • KEAP1 or NFE2L2 mutations that predict poor response to checkpoint inhibitor immunotherapy may also be related to resistance to adagrasib.
  • intrinsic or adaptive resistance may be caused by concurrent genetic changes, such as secondary KRAS mutations and other genetic mutations, which are not targeted by KRAS-G12C inhibitors.
  • KRAS-G12C mutation cancer 27 patients with NSCLC, 10 with colorectal cancer, and 1 with appendix cancer
  • 45%patients are found a putative resistance mechanism to adagrasib.
  • KRAS-Y96D mutation directly affects the binding of adagrasib to the P2 pocket, thereby conferring resistance to sotorasib, adagrasib, or ARS-1620 in multiple cancer cell lines (H358, MIAPaCa2, and BaF3) .
  • RM-018 a representative KRAS-G12C-selective inhibitor from Revolution Medicines’ new class of RAS (ON) inhibitors, retains potent inhibitory activity against tumor cells harboring dual KRAS-G12C/Y92D mutations.
  • KRAS-Y96D KRAS-Y96S and KRAS-Y96C also contribute to the resistance to sotorasib or adagrasib in BaF3 cells, and this process can be reversed by the combined use of SOS1 inhibitors (BI-3406) .
  • SOS1 inhibitors BI-3406
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS.
  • the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS.
  • the individual comprises a R68M, Y96D, or A59T mutation.
  • the cancer comprises a copy number variation in KRAS. In some embodiments, the cancer comprises a copy number in KRAS (e.g., mutant KRAS, e.g., wildtype KRAS) that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%higher than a reference copy number. In some embodiments, the cancer comprises a copy number in KRAS (e.g., mutant KRAS, e.g., wildtype KRAS) that is at least about one-fold, two-fold, three-fold, four-fold, five-fold, six-fold, seven-fold, eight-fold, nine-fold, ten-fold higher than a reference copy number in KRAS.
  • KRAS e.g., mutant KRAS, e.g., wildtype KRAS
  • the reference copy number in KRAS is a corresponding copy number in KRAS of a reference individual (or a population of reference individual) without the disease (e.g., cancer) .
  • the reference copy number in KRAS is a corresponding copy number in KRAS of the same individual prior to the prior therapy (e.g., prior KRAS G12C inhibitor treatment) .
  • the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy.
  • the cancer comprises a KRAS mRNA level and/or KRAS protein level (e.g., mutant KRAS, e.g., wildtype KRAS) that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%higher than a reference KRAS mRNA level and/or KRAS protein level.
  • the cancer comprises a KRAS mRNA level and/or KRAS protein level (e.g., mutant KRAS, e.g., wildtype KRAS) that is at least about one-fold, two-fold, three-fold, four-fold, five-fold, six-fold, seven-fold, eight-fold, nine-fold, ten-fold higher than a reference KRAS mRNA level and/or KRAS protein level.
  • the reference KRAS mRNA level and/or KRAS protein level is a corresponding KRAS mRNA level and/or KRAS protein level of a reference individual (or a population of reference individual) without the disease (e.g., cancer) .
  • the reference KRAS mRNA level and/or KRAS protein level is a corresponding KRAS mRNA level and/or KRAS protein level of the same individual prior to the prior therapy (e.g., prior KRAS G12C inhibitor treatment) .
  • the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter.
  • the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy.
  • the cancer has an increased level of active GTP-bound wildtype RAS.
  • the wildtype RAS comprises H-RAS and/or N-RAS.
  • the individual develops a resistance to KRAS inhibitor that is independent from a MAPK pathway (e.g., when the mRNA level or protein level of a molecule involved in MAPK pathway is not significantly changed, see e.g., Microbiol Mol Biol Rev. 2011 Mar; 75 (1) : 50–83) .
  • the prior KRAS inhibitor is an inhibitor specifically targeting a mutation on codon 12.
  • the KRAS inhibitor is a G12C inhibitor.
  • G12C inhibitors can be found in e.g., J Exp Clin Cancer Res 41, 27 (2022) , which in incorporated herein in its entirety.
  • the KRAS inhibitor is ARS-1620, RM-018, sotorasib or adagrasib.
  • the KRAS inhibitor is a G12D inhibitor.
  • G12D inhibitors can be found in e.g., Cell Discov 8, 5 (2022) , which is incorporated herein in its entirety.
  • the G12D inhibitor is MRTX1133 or RMC-9805.
  • the KRAS inhibitor is a G12V inhibitor.
  • G12V inhibitors can be found in e.g., Cancer Res (2021) 81 (13_Supplement) : 1260, which in incorporated herein in its entirety..
  • the complex is administered at least about 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, or 24 months after the KRAS inhibitor treatment.
  • the complex is administered no more than about 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, or 24 months after the KRAS inhibitor treatment.
  • Mutant KRAS e.g., mutation on codon 12, e.g., secondary mutation post prior KRAS inhibitor treatment
  • the cancer tissue has a KRAS aberration.
  • the aberration of KRAS comprises a mutation on codon 12.
  • the mutation on codon 12 is a somatic mutation.
  • the mutation on codon 12 is a germline mutation.
  • the aberration of KRAS is G12C.
  • the cancer tissue has a KRAS mutation on codon 13, 59, 61, 68, 95, or 96.
  • the cancer tissue has a G12D, G12R, G12V, G12W, G13D, A59T, Q61H, R68S, R68M, H95D, H95Q, H95R, Y96C, Y96D, or high-level amplification of the KRASG12C allele.
  • any one of the mutations on codon 13, 59, 61, 68, 95, and/or 96 are germline mutation.
  • any one of the mutations on codon 13, 59, 61, 68, 95, and/or 96 are somatic mutation.
  • the cancer tissues have a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 12, 13, 59, 61, 68, 95, or 96 after the prior KRAS inhibitor treatment.
  • the cancer tissue has an acquired KRAS aberration selected from the group consisting of G12D, G12R, G12V, G12W, G13D, A59T, Q61H, R68S, R68M, H95D, H95Q, H95R, Y96C, Y96D, and high-level amplification of the KRASG12C allele, optionally the acquired KRAS aberration is developed after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a Q61H mutation after the prior therapy (e.g., a prior KRAS inhibitor treatment) .
  • the cancer tissue has at least one (or at least two, three, four or five) additional KRAS aberration (e.g., one additional mutation) other than G12C.
  • the at least one (or at least two, three, four or five) additional KRAS aberration is selected from the group consisting of G12D, G12R, G12V, G12W, G13D, A59T, Q61H, R68S, R68M, H95D, H95Q, H95R, Y96C, Y96D, and high-level amplification of the KRASG12C allele.
  • the one additional KRAS aberration is Q61H.
  • the sample is a tissue sample or nucleic acids extracted from a tissue sample.
  • the sample is a cell sample (for example a CTC sample) or nucleic acids extracted from a cell sample.
  • the sample is a tumor biopsy.
  • the sample is a tumor sample or nucleic acids extracted from a tumor sample.
  • the sample is a biopsy sample or nucleic acids extracted from the biopsy sample.
  • the sample is a Formaldehyde Fixed-Paraffin Embedded (FFPE) sample or nucleic acids extracted from the FFPE sample.
  • the sample is a blood sample.
  • cell-free DNA is isolated from the blood sample.
  • the biological sample is a plasma sample or nucleic acids extracted from the plasma sample.
  • the genetic aberrations of KRAS may be determined by any method known in the art. See, for example, Dickson et al. Int. J. Cancer, 2013, 132 (7) : 1711-1717; Wagle N. Cancer Discovery, 2014, 4: 546-553; and Cancer Genome Atlas Research Network. Nature 2013, 499: 43-49.
  • Exemplary methods include, but are not limited to, genomic DNA sequencing, bisulfite sequencing or other DNA sequencing-based methods using Sanger sequencing or next generation sequencing platforms; polymerase chain reaction assays; in situ hybridization assays; and DNA microarrays.
  • the epigenetic features (such as DNA methylation, histone binding, or chromatin modifications) of one or more genes from a sample isolated from the individual may be compared with the epigenetic features of the one or more genes from a control sample.
  • the nucleic acid molecules extracted from the sample can be sequenced or analyzed for the presence of the genetic aberrations relative to a reference sequence, such as the wildtype sequences of KRAS.
  • the genetic aberration of KRAS is assessed using cell-free DNA sequencing methods. In some embodiments, the genetic aberration of KRAS is assessed using next-generation sequencing. In some embodiments, the genetic aberration of KRAS isolated from a blood sample is assessed using next-generation sequencing. In some embodiments, the genetic aberration of KRAS is assessed using exome sequencing. In some embodiments, the genetic aberration of KRAS is assessed using fluorescence in-situ hybridization analysis. In some embodiments, the genetic aberration of KRAS is assessed prior to initiation of the methods of treatment described herein. In some embodiments, the genetic aberration of KRAS is assessed after initiation of the methods of treatment described herein. In some embodiments, the genetic aberration of KRAS is assessed prior to and after initiation of the methods of treatment described herein. An aberrant level of KRAS may refer to an aberrant expression level or an aberrant activity level.
  • the individual does not develop a secondary KRAS mutation in exon 1 and/or 2 after the KRAS treatment.
  • the cancer is a leukemia or lymphoma. In some embodiments, the cancer is a solid tumor.
  • the solid tumor includes, but is not limited to, sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, Kaposi's sarcoma, soft tissue sarcoma, uterine sacronomasynovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, me
  • the disease is selected from the group consisting of myelodysplastic syndrome, lung cancer (e.g., NSCLC, small cell lung cancer, squamous cell lung cancer) , colorectal cancer, acute myeloid leukemia, pancreatic cancer, rectal cancer, esophageal squamous cell carcinoma, gastrointestinal stromal tumor, head and neck squamous cancer, pancreatic ductal adenocarcinoma, multiple myeloma, and glioma.
  • lung cancer e.g., NSCLC, small cell lung cancer, squamous cell lung cancer
  • colorectal cancer e.g., acute myeloid leukemia
  • pancreatic cancer rectal cancer
  • esophageal squamous cell carcinoma e.ophageal squamous cell carcinoma
  • gastrointestinal stromal tumor e.g., gastrointestinal stromal tumor
  • head and neck squamous cancer pancreatic ductal aden
  • the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma) .
  • the cancer is colorectal cancer.
  • the cancer is lung cancer (e.g., NSCLC) .
  • the cancer is a malignant and/or advanced cancer.
  • the amount of ERK 1/2 inhibitor, KRAS G12C inhibitor, and/or an EGFR inhibitor (e.g., an anti-EGFR antibody, e.g., cetuximab) which will be effective in the treatment, inhibition and prevention of cancer harboring a KRAS G12C mutation (i.e., a cancer comprising one ore cancer cells that express a KRAS G12C mutant protein) may be determined by standard clinical techniques.
  • the doses of the inhibitors will also depend the concentration of each inhibitor, on the route of administration, and the seriousness of the cancer, the patient’s condition, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • provided herein are methods and/or uses for treating cancer harboring a KRAS G12C mutation (i.e., a cancer comprising one or more cancer cells that express a KRAS G12C mutant protein) in a subject, comprising administering to the subject an effective amount of (1) an ERK 1/2 inhibitor; and (2) a KRAS G12C inhibitor.
  • the method further comprises administering an effective amount of an EGFR inhibitor (e.g., an anti-EGFR antibody, e.g., cetuximab) .
  • an effective amount e.g., dosage
  • the ERK 1/2 inhibitor is the following formula or a pharmaceutically acceptable salt thereof,
  • the amount of ERK 1/2 inhibitor administered to the subject is equivalent to a dose for a mouse which is included in any of the following ranges: about 10 mg/kg to about 100 mg/kg, about 10 to about 25 mg/kg, about 10 to about 30 mg/kg, about 10 mg/kg to about 50 mg/kg, about 20 to about 25 mg/kg, about 20 to about 50 mg/kg, about 25 to about 50 mg/kg, about 25 to about 55 mg/kg, about 20 to about 25 mg/kg, about 40 to about 50 mg/kg, about 30 mg/kg to about 50 mg/kg, about 20 mg/kg to about 60 mg/kg, about 10 mg/kg to about 25 mg/kg, or about 45 mg/kg to about 55 mg/kg.
  • the amount of ERK 1/2 inhibitor administered to the subject for treating cancer is equivalent to a dose for a mouse which includes, for example, any of about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg, about 31 mg/kg, about 32 mg/kg, about 33 mg/kg, about 34 mg/kg, about 35 mg/kg, about 36 mg/kg, about 37 mg/kg, about 38 mg/kg, about 39 mg/kg, about 40 mg/kg, about 41 mg/kg, about 42 mg/kg, about 43 mg/kg, about 44 mg/kg, about 45 mg/kg, about 46 mg/kg, about 47 mg/kg, about 48 mg/kg, about 49 mg/kg, about 50 mg/kg, about 51 mg/kg, about 52 mg/kg, about 53 mg/kg, about 54 mg/kg, about 55 mg/kg, or
  • the ERK 1/2 inhibitor is administered to the subject twice a day, daily, or once every two days. In some embodiments, the ERK 1/2 inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the ERK 1/2 inhibitor is administered twice a day, daily, or once every two days for at least about 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or 52 weeks.
  • the KRAS G12C inhibitor comprises an agent comprising the following formula or a pharmaceutically acceptable salt thereof,
  • the amount of KRAS G12C inhibitor administered to the subject is a dose equivalent to a dose for a mouse that is included in any of the following ranges: about 1 to about 10 mg/kg, about 10 to about 100 mg/kg, about 10 to about 25 mg/kg, about 10 to about 30 mg/kg, about 10 mg/kg to about 50 mg/kg, about 20 to about 25 mg/kg, about 20 to about 50 mg/kg, about 25 to about 50 mg/kg, about 25 to about 55 mg/kg, about 20 to about 25 mg/kg, about 40 to about 50 mg/kg, about 30 mg/kg to about 50 mg/kg, about 20 mg/kg to about 60 mg/kg, about 10 mg/kg to about 25 mg/kg, about 40 mg/kg to about 80 mg/kg, about 5 mg/kg to about 30 mg/kg, about 50 mg/kg to about 100 mg/kg, about 75 mg/kg to about 100 mg/kg, about 80 mg/kg to about 100 mg/kg, 90 mg/kg to about 100 mg/kg, or about 40
  • the dose of the KRAS G12C inhibitor for treating cancer in a subject is a dose equivalent to a dose for a mouse that is for example any of about 3 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg, about 31 mg/kg, about 32 mg/kg, about 33 mg/kg, about 34 mg/kg, about 35 mg/kg, about 36 mg/kg, about 37 mg/kg, about 38 mg/kg, about 39 mg/kg, about 40 mg/kg, about 41 mg/kg, about 42 mg/kg, about 43 mg/kg, about 44 mg/kg, about 45 mg/kg, about 46 mg/kg, about 47 mg/kg, about 48 mg/kg, about 49 mg/kg, about 50 mg/kg, about 51 mg/kg, about
  • the G12C inhibitor is administered to the subject twice a day, daily, or once every two days. In some embodiments, the G12C inhibitor is administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the G12C inhibitor is administered twice a day, daily, or once every two days for at least about 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or 52 weeks.
  • the ERK 1/2 inhibitor is administered orally. In some embodiments, the KRAS G12C inhibitor is administered orally. In some embodiments, the inhibitor or inhibitors are administered twice a day, daily, or once every two days. In some embodiments, the inhibitor or inhibitors are administered twice a day, daily, or once every two days for at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 250, 300, 350, or 365 days. In some embodiments, the inhibitor or inhibitors are administered twice a day, daily, or once every two days for at least about 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or 52 weeks. In some embodiments, the inhibitor or inhibitors are administered twice a day.
  • the inhibitor or inhibitors are administered twice a day for 28 days.
  • the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, mesothelioma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, Hodgkin lymphoma, myeloma, and sarcoma.
  • the cancer is advanced, unresectable, and/or metastatic solid tumor.
  • the cancer is resistant to (e.g., has acquired resistance to) KRAS G12C inhibition (e.g., resistant to a KRAS inhibitor, e.g., resistant to MRTX849, AMG510, or Compound 17) .
  • the cancer is lung cancer.
  • the cancer is colorectal cancer.
  • the cancer is prostate cancer.
  • the cancer was previously treated with a second KRAS G12C inhibitor.
  • the cancer tissues has a secondary mutation in KRAS after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a KRAS mutation on codon 13, 18, 59, 61, 68, 95, 96, 117, or 146 after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a G13C/D, A18D, Q61H/L, A59T, R68S/M, H95D/Q/R, Y96C/D, K117N, and/or A146T mutation after the prior KRAS inhibitor treatment.
  • the cancer tissue developed a R68M, Y96D, or A59T mutation after the prior KRAS inhibitor treatment.
  • the individual comprises a secondary mutation in KRAS, optionally wherein the secondary mutation comprises a R68, Y96, or A59 mutation in KRAS, optionally the individual comprises a R68M, Y96D, or A59T mutation; 2) the cancer comprises a copy number variation in KRAS; 3) the cancer comprises an upregulated KRAS mRNA level and/or KRAS protein relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy; 4) the cancer comprises a mutation in KRAS promoter that increases the strength of the promoter; and/or 5) the cancer comprises an increased wildtype RAS signaling relative to a corresponding tissue or organ in a reference individual, a non-cancer tissue or organ in the same individual, or the same cancer prior to a prior therapy, optionally wherein the cancer has an increased level of active GTP-bound wildtype RAS, optionally wherein the wildtype RAS comprises H-RA
  • the second KRAS inhibitor is sotorasib or adagrasib.
  • the ERK 1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously, concurrently, or sequentially.
  • the ERK 1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • the KRAS G12C inhibitor is administered prior to the ERK 1/2 inhibitor.
  • the method further comprises administering to the individual an effective amount of a third therapy comprising another anti-cancer agent, optionally wherein the anti-cancer agent is selected from the group consisting of an immune checkpoint inhibitor, a cytotoxic agent, a cytostatic agent, an anti-angiogenic agent, a debulking agent, a chemotherapeutic agent, an antibody-drug conjugate, radiotherapy and radiotherapeutic agents, a targeted anti-cancer agent, BRMs, a therapeutic antibody, a cancer vaccine, cytokines, hormone therapies, radiation therapy, and anti-metastatic agents.
  • the anti-cancer agent is selected from the group consisting of an immune checkpoint inhibitor, a cytotoxic agent, a cytostatic agent, an anti-angiogenic agent, a debulking agent, a chemotherapeutic agent, an antibody-drug conjugate, radiotherapy and radiotherapeutic agents, a targeted anti-cancer agent, BRMs, a therapeutic antibody, a cancer vaccine, cytokines, hormone therapies, radiation
  • the ERK1/2 inhibitor is used for the manufacture of a medicament for treating cancer, wherein the treatment is in combination with a KRAS G12C inhibitor.
  • the ERK1/2 inhibitor and the KRAS G12C inhibitor are used for the manufacture of a medicament for treating cancer, wherein the treatment is in combination with a KRAS G12C inhibitor.
  • the treatment comprises administration of the (1) ERK 1/2 inhibitor and the (2) KRAS G12C inhibitor in amounts (e.g., dosages) that can result in the functionality as described herein.
  • the EGFR inhibitor (e.g., an anti-EGFR antibody, e.g., cetuximab) administered to the subject is a dose equivalent to a dose for a mouse that is about 30 mg/kg or at least about 30 mg/kg.
  • the EGFR inhibitor (e.g., an anti-EGFR antibody, e.g., cetuximab) is administered intravenously or subcutaneously.
  • the EGFR inhibitor (e.g., an anti-EGFR antibody, e.g., cetuximab) is administered at a frequency of twice a day, daily, or once every two days.
  • the EGFR inhibitor (e.g., an anti-EGFR antibody, e.g., cetuximab) is administered at a frequency of no more than twice a day, daily, or once every two days.
  • treatment according to any of the methods or uses disclosed herein results in at least about a 2 fold, about a 2.5 fold, about a 3 fold, about a 3.5 fold, about a 4 fold, about a 4.5 fold, about a 5 fold, about a 5.5 fold, about a 6 fold, about a 6.5 fold, about a 7 fold, about a 7.5 fold, about a 8 fold, about a 8.5 fold, about a 9 fold, about a 9.5 fold, about a 10 fold, about a 10.5 fold, about a 11 fold, about a 12 fold, about a 15 fold, about a 18 fold, about a 20 fold, about a 21 fold, about a 22 fold, about a 23 fold, about a 24 fold, about a 25 fold, about a 26 fold, about a 27 fold, about a 28 fold, about a 29 fold, about a 30 fold, about a 31 fold, about a 32 fold, about a 33 fold, about a 34 fold, or about a
  • treatment according to any of the methods or uses disclosed herein results in at least about a 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 33.3%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%
  • treatment according to any of the methods or uses disclosed herein results in at least about a 2 fold, about a 2.5 fold, about a 3 fold, about a 3.5 fold, about a 4 fold, about a 4.5 fold, about a 5 fold, about a 5.5 fold, about a 6 fold, about a 6.5 fold, about a 7 fold, about a 7.5 fold, about a 8 fold, about a 8.5 fold, about a 9 fold, about a 9.5 fold, about a 10 fold, about a 12 fold, about a 14 fold, about a 16 fold, about a 18 fold, or about a 20 fold decrease in tumor weight compared to tumors that are not treated according to any of the methods or uses disclosed herein.
  • treatment according to any of the methods or uses disclosed herein results in at least about a 2 fold, about a 2.5 fold, about a 3 fold, about a 3.5 fold, about a 4 fold, about a 4.5 fold, about a 5 fold, about a 5.5 fold, about a 6 fold, about a 6.5 fold, about a 7 fold, about a 7.5 fold, about a 8 fold, or about a 8.5 fold decrease in tumor weight compared to tumors that are not treated according to any of the methods or uses disclosed herein.
  • treatment according to any of the methods or uses disclosed herein results in at least about a 2 fold, about a 2.5 fold, about a 3 fold, about a 3.5 fold, about a 4 fold, about a 4.5 fold, about a 5 fold, about a 5.5 fold, about a 6 fold, about a 6.5 fold, about a 7 fold, about a 7.5 fold, about a 8 fold, or about a 8.5 fold increase in survival in subjects (e.g., individuals) compared to the subjects (e.g., individuals) that are not treated according to any of the methods or uses disclosed herein (e.g., single therapy or vehicle control) .
  • kits comprising materials useful for the treatment of a KRAS G12C mutant cancer (such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma) .
  • the kit comprises a container containing an ERK 1/2 inhibitor as described herein, and a second container comprising a KRAS G12C inhibitor.
  • kits comprising materials useful for the treatment of a KRAS G12C mutant cancer (such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma) .
  • a KRAS G12C mutant cancer such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer,
  • the kit comprises a container containing an ERK 1/2 inhibitor as described herein, and a second container comprising a KRAS G12C inhibitor.
  • ERK 1/2 inhibitor comprises an agent comprising formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n is 0 or 1;
  • m is 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R d ;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1-3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • kits comprising materials useful for the treatment of a KRAS G12C mutant cancer (such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma) .
  • the kit comprises a container containing an ERK 1/2 inhibitor as described herein, and a second container comprising a KRAS G12C inhibitor.
  • ERK 1/2 inhibitor comprises an agent comprising the following formula
  • kits comprising materials useful for the treatment of a KRAS G12C mutant cancer (such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma) .
  • a KRAS G12C mutant cancer such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer,
  • the kit comprises a container containing an ERK 1/2 inhibitor as described herein, and a second container comprising a KRAS G12C inhibitor.
  • the KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from O and N; R 1 is selected from C 6-10 aryl and 5-to 10-membered heteroaryl, wherein the C 6-10 aryl and 5-to 10-membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 Ra; when T 1 is O, R 2 is not present; when T 1 is N, R 2 is selected from H, C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1-3 alkyl, wherein the C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1-3 alkyl are optionally substituted with 1, 2 or 3 R b ; R 3 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ; R 4 is selected from H and C 1-3 alkyl, wherein the C 1- 3 alkyl is optionally substituted with 1, 2 or 3
  • kits comprising materials useful for the treatment of a KRAS G12C mutant cancer (such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma) .
  • the kit comprises a container containing an ERK 1/2 inhibitor as described herein, and a second container comprising a KRAS G12C inhibitor; and wherein the KRAS G12C inhibitor comprises an agent comprising the following formula
  • kits comprising materials useful for the treatment of a KRAS G12C mutant cancer (such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma) .
  • a KRAS G12C mutant cancer such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer,
  • the kit comprises a container containing an ERK 1/2 inhibitor as described herein, and a second container comprising a KRAS G12C inhibitor.
  • ERK 1/2 inhibitor comprises an agent comprising the following formula or a pharmaceutically acceptable salt thereof,
  • KRAS G12C inhibitor comprises an agent comprising the following formula
  • the kit comprises a container and a label or package insert on or associated with the containers.
  • Suitable containers include, for example, bottles, vials, syringes, IV solution bags, test tubes, etc.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the first container holds a composition (e.g., a composition comprising an ERK 1/2 inhibitor as described herein) which is by itself or combined with another composition effective for treating (such as delaying the progression of) a KRAS G12C mutant cancer (such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma) .
  • a KRAS G12C mutant cancer such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal a
  • the container may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle) .
  • a sterile access port for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle.
  • At least one agent in the composition is an ERK 1/2 inhibitor as described herein. In some embodiments, the at least one agent in the composition is an ERK 1/2 inhibitor as described herein.
  • the label or package insert indicates that the composition is used in combination with a KRAS G12C inhibitor for treating a KRAS G12C mutant cancer (such as lung adenocarcinoma, non-small cell lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, peritoneal cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma) .
  • the KRAS G12C inhibitor is Compound 17.
  • the kit may comprise (a) a first container with a composition contained therein, wherein the composition comprises an ERK 1/2 inhibitor as described herein, and (b) a second container with a composition contained therein, wherein the composition comprises KRAS G12C inhibitor (e.g., a polypeptide, antibody, fusion polypeptide, antisense oligonucleotide or a small molecule drug that is capable of inhibiting the activity of the KRAS G12C mutant protein) .
  • the second container contains a small molecule KRAS G12C inhibitor.
  • Exemplary small molecule KRAS G12C inhibitors that can be packaged with the kits provided herein include, without limitation, e.g., sotorasib, adagrasib, JAB-21822, GDC-6036, JDQ443, D-1553, GH35, GFH925, BPI-421286, and LY3537982, RMC-6291, RMC-8839, HBI-2438, JNJ-74699157, and Compound 17.
  • the KRAS G12C inhibitor is Compound 17.
  • kit may further comprise an additional container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI) , phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
  • a pharmaceutically-acceptable buffer such as bacteriostatic water for injection (BWFI) , phosphate-buffered saline, Ringer's solution and dextrose solution.
  • Embodiment 1 A method of treating cancer in an individual, comprising administering to the individual an effective amount of 1) an ERK1/2 inhibitor; and 2) a KRAS G12C inhibitor, wherein the ERK1/2 inhibitor comprises an agent comprising the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n 0 or 1
  • n 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1- 3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • Embodiment 2 The method of embodiment 1, wherein the ERK1/2 inhibitor is selected from:
  • Embodiment 3 The method of embodiment 2, wherein the ERK1/2 inhibitor comprises an agent comprising the following formula or a pharmaceutically acceptable salt thereof,
  • Embodiment 4 The method of any one of embodiments 1-3, wherein the KRAS G12C inhibitor is a small molecule.
  • Embodiment 5 The method of embodiment 4, wherein the KRAS G12C inhibitor is selected from the group consisting of: sotorasib, adagrasib, JAB-21822, GDC-6036, JDQ443, D-1553, GH35, GFH925, BPI-421286, and LY3537982, RMC-6291, RMC-8839, HBI-2438, and JNJ-74699157.
  • Embodiment 6 The method of embodiment 5, wherein the KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from O and N;
  • R 1 is selected from C 6-10 aryl and 5-to 10-membered heteroaryl, wherein the C 6-10 aryl and 5-to 10-membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 R a ;
  • R 2 is selected from H, C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1-3 alkyl, wherein the C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1-3 alkyl are optionally substituted with 1, 2 or 3 R b ;
  • R 3 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 4 is selected from H and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
  • R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 F;
  • R 8 is selected from H and CH 3 ;
  • R a is each independently selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1- 3 alkoxy, C 2-3 alkynyl and C 2-3 alkenyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl and C 2- 3 alkenyl are optionally substituted with 1, 2 or 3 F;
  • R b is each independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R c is each independently selected from 4-to 8-membered heterocycloalkyl, wherein the 4-to 8-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
  • R d is each independently selected from F, Cl, Br, I, OH, NH 2 and CN;
  • R is each independently selected from H, F, Cl, Br, OH, CN, C 1-3 alkyl, C 1-3 alkoxy and -C 1-3 alkyl-O-C ( ⁇ O) -C 1-3 alkylamino;
  • R 1 is naphthyl
  • the naphthyl is optionally substituted with F, Cl, Br, OH, NH2, CF 3 , CH 2 CH 3 and -C ⁇ CH
  • R 5 , R 6 and R 7 are each independently H.
  • Embodiment 7 A method of treating cancer in an individual, comprising administering to the individual an effective amount of 1) an ERK1/2 inhibitor; and 2) KRAS G12C inhibitor, wherein the KRAS G12C inhibitor comprises an agent comprising formula (III) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from O and N;
  • R 1 is selected from C 6-10 aryl and 5-to 10-membered heteroaryl, wherein the C 6-10 aryl and 5-to 10-membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 R a ;
  • R 2 is selected from H, C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1-3 alkyl, wherein the C 1-3 alkyl, -C ( ⁇ O) -C 1-3 alkyl and -S ( ⁇ O) 2 -C 1-3 alkyl are optionally substituted with 1, 2 or 3 R b ;
  • R 3 is C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 4 is selected from H and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R d ;
  • R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 F;
  • R 8 is selected from H and CH 3 ;
  • R a is each independently selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1- 3 alkoxy, C 2-3 alkynyl and C 2-3 alkenyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl and C 2- 3 alkenyl are optionally substituted with 1, 2 or 3 F;
  • R b is each independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R c is each independently selected from 4-to 8-membered heterocycloalkyl, wherein the 4-to 8-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;
  • R d is each independently selected from F, Cl, Br, I, OH, NH 2 and CN;
  • R is each independently selected from H, F, Cl, Br, OH, CN, C 1-3 alkyl, C 1-3 alkoxy and -C 1-3 alkyl-O-C ( ⁇ O) -C 1-3 alkylamino;
  • R 1 is naphthyl
  • the naphthyl is optionally substituted with F, Cl, Br, OH, NH 2 , CF 3 , CH 2 CH 3 and -C ⁇ CH
  • R 5 , R 6 and R 7 are each independently H.
  • Embodiment 8 The method of embodiment 7, wherein the KRAS G12C inhibitor comprises an agent comprising the following formula
  • Embodiment 9 The method of embodiment 8, wherein the KRAS G12C inhibitor comprises an agent comprising the following formula
  • Embodiment 10 The method of any one of embodiments 7-9, wherein the ERK1/2 inhibitor is a small molecule.
  • Embodiment 11 The method of embodiment 10, wherein the ERK1/2 inhibitor is selected from the group consisting of: BVD-523 (ulixertinib) , CC-90003, GDC-0994 (Ravoxertinib) , KO-947, LTT462, LY3214996 (temuterkib) , WX001, SCH772984, FR180204, and MK-8353.
  • the ERK1/2 inhibitor is selected from the group consisting of: BVD-523 (ulixertinib) , CC-90003, GDC-0994 (Ravoxertinib) , KO-947, LTT462, LY3214996 (temuterkib) , WX001, SCH772984, FR180204, and MK-8353.
  • Embodiment 12 The method of embodiment 10, wherein the ERK1/2 inhibitor comprises an agent comprising the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
  • R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c substitution;
  • n 0 or 1
  • n 1 or 2;
  • Ring A is selected from pyrazolyl and tetrahydropyranyl optionally substituted with 1, 2 or 3 R;
  • R a and R c are independently selected from D, F, Cl, Br and I;
  • R d is selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and said C 1-3 alkyl and C 1- 3 alkoxy are optionally replaced by 1, 2 or 3 R substitutions;
  • R is selected from F, Cl, Br and I.
  • Embodiment 13 The method of any one of embodiments 1-12, wherein the KRAS G12C inhibitor is administered orally.
  • Embodiment 14 The method of any one of embodiments 1-13, wherein the ERK1/2 inhibitor is administered orally.
  • Embodiment 15 The method of any one of embodiments 1-14, wherein the cancer comprises one or more cancer cells that express a KRAS G12C mutant protein.
  • Embodiment 16 The method of any one of embodiments 1-15, wherein the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, mesothelioma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, Hodgkin lymphoma, myeloma, and sarcoma.
  • the cancer is colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma,
  • Embodiment 17 The method of any one of embodiments 1-16, wherein the cancer is a solid tumor, optionally wherein the solid tumor is an advanced, unresectable, and/or metastatic solid tumor.
  • Embodiment 18 The method of any one of embodiments 1-17, wherein the cancer is resistant to KRAS G12C inhibition, optionally wherein the cancer is resistant to a KRAS G12C inhibitor (e.g., MRTX849, e.g., AMG510) .
  • a KRAS G12C inhibitor e.g., MRTX849, e.g., AMG510
  • Embodiment 19 The method of any one of embodiments 1-18, wherein the cancer was previously treated with a KRAS G12C inhibitor.
  • Embodiment 20 The method of embodiment 19, wherein the KRAS12C inhibitor is sotorasib.
  • Embodiment 21 The method of any one of embodiments 1-20, wherein the ERK1/2 inhibitor and the KRAS G12C inhibitor are administered simultaneously.
  • Embodiment 22 The method of any one of embodiments 1-21, wherein the ERK1/2 inhibitor and the KRAS G12C inhibitor are administered concurrently.
  • Embodiment 23 The method of any one of embodiments 1-20, wherein the ERK1/2 inhibitor and the KRAS G12C inhibitor are administered sequentially.
  • Embodiment 24 The method of embodiment 23, wherein the ERK1/2 inhibitor is administered prior to the KRAS G12C inhibitor.
  • Embodiment 25 The method of embodiment 23, wherein the KRAS G12C inhibitor is administered prior to the ERK1/2 inhibitor.
  • Embodiment 26 The method of any one of embodiments 1-25, wherein the ERK 1/2 inhibitor is administered in one or more doses.
  • Embodiment 27 The method of embodiment 26, wherein the dose is equivalent to a dose of about 10 mg/kg to about 100 mg/kg for a mouse.
  • Embodiment 28 The method of any one of embodiments 1-27, wherein the KRAS G12C inhibitor is administered in one or more doses.
  • Embodiment 29 The method of embodiment 28, wherein the dose is equivalent to a dose of about 10 mg/kg to about 50 mg/kg for a mouse.
  • Embodiment 30 The method of any one of embodiments 1-29, further comprising administering to the individual an effective amount of a third therapy.
  • Embodiment 31 The method of embodiment 30, wherein the third therapy comprises another anti-cancer agent.
  • Embodiment 32 The method of embodiment 31, wherein the anti-cancer agent is selected from the group consisting of an immune checkpoint inhibitor, a cytotoxic agent, a cytostatic agent, an anti-angiogenic agent, a debulking agent, a chemotherapeutic agent, an antibody-drug conjugate, radiotherapy and radiotherapeutic agents, a targeted anti-cancer agent, BRMs, a therapeutic antibody, a cancer vaccine, cytokines, hormone therapies, radiation therapy, and anti-metastatic agents, optionally wherein the anti-cancer agent is an EGFR inhibitor, further optionally wherein the EGFR inhibitor is an anti-EGFR antibody (e.g., cetuximab) .
  • an immune checkpoint inhibitor e.g., a cytotoxic agent, a cytostatic agent, an anti-angiogenic agent, a debulking agent, a chemotherapeutic agent, an antibody-drug conjugate, radiotherapy and radiotherapeutic agents, a targeted anti-cancer agent, BRM
  • Embodiment 33 The method of any one of embodiments 1-32, wherein the individual is a human.
  • Embodiment 34 The method of any one of embodiments 1-33, wherein the method comprises selecting the individual for treatment based on the presence of one or more cancer cells that comprises an aberration in KRAS (e.g., KRAS G12C, e.g., KRAS G12D, e.g., KRAS Q61H) , optionally wherein the aberration in KRAS comprises a) a KRAS G12C mutant protein, b) a KRAS G12D mutant protein and/or c) a KRAS Q61H mutant protein.
  • KRAS e.g., KRAS G12C, e.g., KRAS G12D, e.g., KRAS Q61H
  • the aberration in KRAS comprises a) a KRAS G12C mutant protein, b) a KRAS G12D mutant protein and/or c) a KRAS Q61H mutant protein.
  • Embodiment 35 Use of an ERK1/2 inhibitor and a KRAS G12C inhibitor for the manufacture of a medicament for treating cancer.
  • Embodiment 36 The use of embodiment 35, wherein the cancer is selected from colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, leukemia, uterine cancer, cervical cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, gastric cancer, colorectal cancer, kidney cancer, clear cell renal carcinoma, head and neck cancer, germ cell cancer, bone cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, mesothelioma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, Hodgkin lymphoma, myeloma, and sarcoma.
  • the cancer is selected from colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma, bladder cancer, renal cell carcinoma, liver cancer, prostate cancer, stomach cancer, pancreatic cancer, lymphoma, le
  • Embodiment 37 The method of embodiment 16 or the use of embodiment 36, wherein the cancer is colorectal cancer (e.g., NSCLC) .
  • the cancer is colorectal cancer (e.g., NSCLC) .
  • Embodiment 38 The method of embodiment 16 or the use of embodiment 36, wherein the cancer is pancreatic cancer.
  • Embodiment 39 The method of embodiment 16 or the use of embodiment 36, wherein the cancer is lung cancer.
  • Embodiment 40 The method or use of any one of embodiments 1-39, wherein the treatment comprises a dose that is equivalent to a dose of 25 to 50 mg/kg of the ERK 1/2 inhibitor for a mouse.
  • Embodiment 41 The method or use of any one of embodiments 1-40, wherein the treatment comprises a dose that is equivalent to a dose of 10 to 100 mg/kg of the KRAS G12C inhibitor.
  • Embodiment 42 A kit for treating cancer in an individual, comprising: 1) an ERK1/2 inhibitor; and 2) a KRAS G12C inhibitor.
  • Example 1 Evaluation of the anti-tumor efficacy of ERK1/2 inhibitor in combination with KRAS G12C inhibitor in NCI-H2122 human lung cancer xenograft mouse model.
  • the objective was to evaluate the in vivo anti-tumor efficacy of WX001 (i.e., WX001; ERK1/2 inhibitor) in combination with Compound 17 (KRAS G12C inhibitor) in subcutaneous NCI-H2122 human lung cancer xenograft implanted in female BALB/c nude mice.
  • WX001 i.e., WX001; ERK1/2 inhibitor
  • Compound 17 KRAS G12C inhibitor
  • WX001 is administered on a simple and continuous QD schedule without dosing holidays as described below, allowing a simple protocol that is convenient for patients.
  • WX001 While several potent ERK inhibitors, such as AZD0364, ERAS007, and MK-8353, have relatively long target protein-residence times (ranging from 190 to 550 minutes) , the ERK protein residence time for WX001 is approximately 40 minutes. Inventors’ have unique insights that WX001’s intermediate protein residency time is more favorable because it is long enough to allow sufficient target blockade while short enough to permit pulsatile inhibition, which will help alleviate on-target toxicity in normal tissues. The clinical PK of WX001 is around 3-6 hours, further supporting an intermittent target inhibition profile when dosed once daily, twice a day or once every two days.
  • NCI-H2122 tumor cells (ATCC, cat#CRL-5985) were maintained in RPMI 1640 medium supplemented with 10%fetal bovine serum and 1%PS can cultures in an incubator set at 37°C with 5%CO 2 .
  • the tumor cells were routinely sub-cultured twice weekly.
  • the cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
  • mice Female BALB/c nude mice were inoculated subcutaneously at the right flank with NCI-H2122 tumor cells (5 ⁇ 10 6 ) in 0.2 mL of PBS with Matrigel (1: 1) for tumor development. Treatments were started on day 6 after tumor inoculation when the average tumor volume reached 159 mm 3 . The animals were assigned into groups using an Excel-based randomization software performing stratified randomization based upon their tumor volumes. Each group consisted of 6 tumor-bearing mice. The testing articles were prepared and were administrated to the mice according to the predetermined regimen as shown in the experimental design table (Tables E1) .
  • QD daily
  • BID two times a day.
  • TGI Tumor Growth Inhibition
  • One-way ANOVA was performed to compare the tumor volume among groups, followed by Dunnet’s multiple comparisons. All data were analyzed using Graphpad Prism software. A p ⁇ 0.05 was considered to be statistically significant.
  • mice bearing the NCI-H2122 xenograft in general can lose over 15%of body weight as tumor progression, thus all mice were supplied with nutrient gel and sunflower seeds.
  • NCI-H2122 is a non-small cell lung cancer (NSCLC) cell line harboring KRAS G12C mutation.
  • NCI-H2122 model represents a cancer phenotype that is partially sensitive to KRAS G12C inhibitors, such as MRTX849.
  • MRTX849 KRAS G12C inhibitors
  • the anti-tumor efficacy of WX001 in combination with Compound 17 was evaluated in NCI-H2122 cell line-derived xenograft model.
  • Two clinical-stage KRAS G12C inhibitors, AMG510 and MRTX849 were included as monotherapy control arms. The efficacy of WX001 monotherapy at two different dose levels was also evaluated.
  • Table E3 Tumor volume over time Note: 1. Data was shown as mean ⁇ SEM; 2. Days refer to the day post treatment initiation.
  • Table E4 Tumor growth inhibition analysis for each treatment in the NCI-H2122 xenograft model calculated based on tumor volume measurements on Day 28 Note: 1. Mean ⁇ SEM;
  • TGI (%) [1- (T 28 -T 0 ) / (V 28 -V 0 ) ] ⁇ 100%;
  • Table E5 Statistical analysis of the difference between Compound 17 monotherapy and combination therapy of Compound 17 with WX001 Note: Calculated based on tumor volume measurements on Day 28.
  • Table E6 The average weight of isolated tumors from each group on day 28 Note: 1. Mean ⁇ SEM;
  • T/C % T/C ⁇ 100 % (T: treatment group; C: control group, T and C are the mean tumor weight of the treated and control groups, respectively, on a given day) ; 3. p value was calculated based on tumor weight.
  • tumor regression was often observed in other KRAS G12C models at this dose level (100 mg/kg) for both AMG510 and MRTX849, only significant tumor growth inhibition, no such effect on tumor regression, was observed in the NCI-H2122 model.
  • mice Animal body weight was monitored regularly as an indirect measure of toxicity. As historical data showed that NCI-H2122 bearing mice might lose over 15%of body weight as tumor progression, all mice were supplied with nutrient gel and sunflower seeds. Two, one and two mice in Vehicle group showed body weight loss>15%on PG-D14, PG-D21 and PG-D28 respectively.
  • One mouse in Group 5 Compound 17, 100 mg/kg, QD
  • one mouse in Group 6 WX001, 25 mg/kg, BID
  • one mouse in Group 9 Compound 17+WX001, 30 mg/kg+25 mg/kg, QD+BID
  • mice in Group 6 WX001, 25 mg/kg, BID
  • mice in Group 7 WX001, 25 mg/kg, QD
  • mice in Group 8 WX001, 50 mg/kg, QD
  • mice in Group 9 Compound 17+WX001, 30 mg/kg +25 mg/kg, QD+BID
  • Example 2 Evaluation of the anti-tumor efficacy of ERK1/2 inhibitor in combination with KRAS G12C inhibitor in SW-837 human colorectal cancer xenograft mouse model.
  • the objective of this study was to evaluate preclinically the in vivo therapeutic efficacy of WX001 in combination with Compound 17, a KRAS G12C inhibitor currently in clinical development, in the treatment of human colorectal cancer xenograft model SW-837, a cell line-derived xenograft model harboring KRAS G12C mutation.
  • the anti-tumor efficacy of Compound 17 or WX001 each as a single agent in this model is also evaluated in comparison to combination treatment.
  • SW-837 tumor cells were maintained in vitro with L-15 (100%air) medium supplemented with 10%fetal bovine serum at 37°C in an atmosphere of 5%CO 2 in the air.
  • the cells in exponential growth phase were harvested and quantitated by cell counter before tumor inoculation.
  • Each mouse was inoculated subcutaneously in the right lower flank region with SW- 837 tumor cells (5 ⁇ 10 6 cells/mouse) in 0.1 ml of PBS mixed with Matrigel (1: 1) for tumor development.
  • the randomization started when the mean tumor size reaches approximately 144 mm 3 .
  • a total of 48 mice were enrolled in the study. All animals were randomly allocated to 6 study groups, 8 mice in each group. Randomization was performed based on “Matched distribution” method (StudyDirector TM software, version 3.1.399.19) . Dosing was implemented right after randomization on Day 0. The treatment was initiated on the same day of randomization (Day 0) as per the study design (Table E7) .
  • the treatment started when the mean tumor volume reached around 144 mm 3 .
  • the experiment was performed for a total of 41 days (Day 0 to Day 40) after randomization, including the efficacy study from Day 0 to Day 39.
  • On Day 40 plasma sampling was performed after one final dose on the day.
  • Tumor Growth Inhibition (TGI) calculation was based on Day 39, the end of the efficacy study.
  • the date of randomization was denoted as day 0.
  • the study was terminated on the day determined by the sponsor or treated until the tumor size of individual mouse exceeding 3000mm 3 .
  • the study was terminated on the specified day post the randomization when the tumor volume of individual mouse met the humane endpoint and as requested by the sponsor.
  • the treatment was performed for 41 days starting from grouping (from Day 0 to Day 40) , and the mice were sacrificed on Day 41.
  • Bartlett's test was first used to check the assumption of homogeneity of variance across all groups.
  • a one-way ANOVA was run to test overall equality of means across all groups. If the p-value of the one-way ANOVA was ⁇ 0.05, further post hoc testing was performed by running Tukey's HSD (honest significant difference) tests for all pairwise comparisons, and Dunnett's tests for comparing each treatment group with the vehicle group.
  • Tukey's HSD nonest significant difference
  • test compounds Compound 17 KRAS G12C inhibitor
  • WX001 ERK1/2 inhibitor
  • WX001 at 25 mg/kg or 50 mg/kg in combination with Compound 17 at 10 mg/kg demonstrated significantly more potent anti-tumor efficacy compared with Compound 17 at 10 mg/kg alone (both p ⁇ 0.001 vs. Compound 17 monotherapy group) , with TGI values of 104.58%and 105.11%, respectively (Table E9, FIG. 6A) .
  • WX001 at 25 mg/kg or 50 mg/kg in combination with Compound 17 at 10 mg/kg demonstrated significantly deeper anti-tumor response with -77.45%and -86.64%tumor regression from baseline, respectively, while Compound 17 at 10 mg/kg alone resulted in -15.02%tumor regression from baseline.
  • Cetuximab + Compound 17, or triplet combination of Cetuximab+Compound 17+WX001 all improved event-free survival. Strikingly, triplet combination of Cetuximab+Compound 17 (30mg/kg) +WX001 (25mg/kg BID) achieved 100%complete tumor remission with no tumor re-growth even thirty days after treatment had stopped, suggesting that the triple combination achieved a durable anti-tumor efficacy. See FIGs. 6C-6D.
  • Example 3 Evaluation of the anti-tumor efficacy of ERK1/2 inhibitor in combination with KRAS G12C inhibitor in CR9537 colorectal cancer xenograft mouse model.
  • the objective of this study is to evaluate the in vivo therapeutic efficacy of test articles Compound 17, WX001 and a reference compound MRTX849 (adagrasib) as a monotherapy and/or in combination with cetuximab in colorectal cancer patient-derived xenograft model CR9537.
  • PDX Patient-derived xenografts
  • the CR9537 PDX model (Crown Biosciences) is established from biopsy samples of a patient with KRAS G12C mutant colorectal cancer.
  • the patient was enrolled in a clinical trial of MRTX849 after the disease progressed on front-line and second-line chemotherapy.
  • the patient eventually became resistant to MRTX849 treatment.
  • Genetic analysis of tumor tissue biopsy from this patient identified acquired KRAS Q61H mutation, indicating the resistant mechanism is due to secondary KRAS mutation.
  • PDX patient-direved xenograft
  • the study design including groups of mice, number of mice per group and treatment, was summarized in the following table. Tumor growth was monitored over time after treatment.
  • mice A total of 66 mice were enrolled in the study. All animals were randomly allocated to 11 study groups, 6 mice in each group. Randomization was performed based on “Matched distribution” method (StudyDirectorTM software, version 3.1.399.19) . The day of randomization was denoted as Day 0. Treatment (Table E10) initiated on the same day of randomization (Day 0) . The treatment started when the mean tumor volume reached around 145 mm 3 . Tumor Growth Inhibition (TGI) calculation was based on the day when the first mouse in vehicle group had to be euthanized due to tumor volume exceeding 3000 mm 3 , a predefined humane endpoint. The treatment was performed for 64 days starting from grouping (from Day 0 to Day 63) , and the remaining mice were sacrificed on Day 63.
  • TGI Tumor Growth Inhibition
  • Dosing as well as tumor and body weight measurements were conducted in a Laminar Flow Cabinet. The body weights and tumor volumes were measured by using StudyDirector TM software (version 3.1.399.19) .
  • Bartlett's test was first used to check the assumption of homogeneity of variance across all groups.
  • the one-way ANOVA was performed to test overall equality of means across all groups. If the p-value of the one-way ANOVA was ⁇ 0.05, post hoc testing was performed by running Tukey's HSD (honest significant difference) tests for all pairwise comparisons, and Dunnett's tests for comparing each treatment group with the vehicle group.
  • a Kruskal-Wallis test was performed to test overall equality of medians among all groups.
  • WX001 in combination with a) MRTX849 and b) Compound 17 respectively produced statistically significant anti-tumor efficacy in the subcutaneous xenograft model CR9537, with TGI values of 86.56%and 74.19% (P ⁇ 0.001 vs. vehicle control) (Table E12, FIG. 7) , demonstrating a consistent better effect than a) cetuximab and MRTX849 with TGI values of 70.26%and b) cetuximab in combination with Compound 17 with TGI values of 72.82%.
  • the combination of MRTX849 and Compound 17 achieved a TGI that is 23%higher than the combination of MRTX849 and cetuximab.
  • Example 4 Evaluation of the anti-tumor efficacy of ERK1/2 inhibitor in combination with KRAS G12C inhibitors in AMG510 resistant Mia PaCa-2 human pancreatic cancer xenograft mouse model.
  • AMG510-R-xMIA PaCa-2 clone #2 was a single clone cell line picked from AMG510-R-xMiaPaCa-2 (CP2) cell population. This cell line was derived from a AMG510-R-MIA PaCa-2 (CP2) resistant tumor, which was induced by continuous treatment of AMG-510 in MIA PaCa-2 human pancreatic cancer xenograft model. KRAS gene amplification was identified by RNAseq and WES analysis in AMG510-R-xMIA PaCa-2 clone #2.
  • the AMG510-R-xMia PaCa-2 (CP2) clone #2 tumor cells were maintained in DMEM/F12 medium supplemented with 10%fetal bovine serum, 1%Antibiotic-Antimycotic, 1 ⁇ M AMG510, at 37 °C in an atmosphere of 5%CO 2 in air.
  • the tumor cells were routinely subcultured twice weekly by trypsin-EDTA treatment.
  • the cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
  • mice Each mouse was inoculated subcutaneously at the right flank with AMG510-R-xMia PaCa-2 (CP2) clone #2 tumor cells (1 x 10 6 ) in 0.2 mL of PBS with for tumor development. Treatments were started when the average tumor size reached approximately 128 mm 3 . The animals were assigned into 8 groups using an Excel-based randomization software performing stratified randomization based upon their tumor volumes. Each group consisted of 8 tumor-bearing mice. The testing articles were administrated to the mice according to the predetermined regimen as shown in Table E13. Dosing volume was adjusted dosing volume based on body weight (10 ⁇ L/g) .
  • T/C (%) T RTV /C RTV x 100 %; T RTV is mean relative tumor volume of treatment group, and C RTV is mean relative tumor volume of control group.
  • Table E15 Mean tumor volume over time a. Mean ⁇ SEM b. Days after treatment. c. Mice with tumor volumes greater than 3000mm 3 were euthanized.
  • a statistically significant difference in survival time was observed in Compound 17 (30 mg/kg) , Compound 17+WX001 (30+25 mg/kg) , and Compound 17+WX001 (30+50 mg/kg) treated groups when compared with Vehicle group (all p values 0.0001) (FIG. 12) .
  • Mouse body weight was monitored regularly as an indirect measure of toxicity.
  • Mouse #706789 and mouse #706803 in Group 4 (Compound 17, 30 mg/kg) showed body weight loss over 15%on day 52 and recovered within 3 days.
  • Mouse #706744 in Group 8 (Compound 17+WX001, 30+50 mg/kg) showed body weight loss over 15%on day 45 and recovered within 3 days;
  • Mouse #706736 in Group 8 (Compound 17+WX001, 30+50 mg/kg) showed body weight loss over 15%on day 105 and was sacrificed on day 105 (the end time point of the study) . No severe body weight loss (>15%) was observed in other groups.
  • Table E17 Kaplan-Meier survival analysis for test compounds in the AMG510-R-xMia PaCa-2 clone #2 xenograft model calculated based on survival data up to day 105 a. All data were analyzed using GraphPad Prism 8.0. Comparisons between groups were carried out with Log-rank test (compared with control group) .
  • Table E18 Statistical Analysis of Difference among Treatment Groups a. Pairwise compared between each group using Log-Rank test.
  • WX001 has demonstrated favorable selectivity in Kinome profiling and follow-up IC50 assays. See FIGs. 14A-14C.
  • WX001 effectively inhibited downstream signaling pathway and cancer cell proliferation with improved potency when compared with two other clinical stage ERK1/2 inhibitors.
  • WX001 demonstrated potent anti-tumor effects in cancers harboring KRAS mutations (G13C, G13D) .
  • Example 6 Evaluation of anti-tumor efficacy of ERK1/2 inhibitor in combination with KRAS G12C inhibitor in NCI-H358 NSCLC xenograft mouse model.
  • Example 7 Evaluation of the anti-tumor efficacy of Compound 17 and WX001 combination therapy in NCI-H1373 human lung cancer xenograft mouse model.
  • the objective was to evaluate the in vivo anti-tumor efficacy of MRTX849 (KRAS G12C inhibitor) , Compound 17 (KRAS G12C inhibitor) , WX001 (ERK 1/2 inhibitor) in subcutaneous NCI-H1373 human lung cancer xenograft implanted in female BALB/c nude mice after they became resistant to KRAS G12C inhibitor.
  • NCI-H1373 human lung cancer cells were maintained in vitro in RPMI-1640 cell culture media supplemented with 10%fetal bovine serum and 1%anti-mycotic/anti-biotic at 37°Cin an atmosphere of 5%CO2 in air.
  • the tumor cells will be routinely sub-cultured twice weekly by trypsin-EDTA treatment. Cells growing in an exponential growth phase are harvested and counted for tumor inoculation.
  • Each BALB/c nude mouse was inoculated subcutaneously at the right flank with NCI-H1373 tumor cells (5 ⁇ 10 6 ) in 0.2 mL of PBS with Matrigel (1: 1) for tumor development. Treatments were started on day 5 after tumor inoculation when the average tumor volume reached an average volume of 198 mm 3 .
  • the animals were randomly assigned into groups based upon their tumor volumes. Each group consisted of 6 tumor-bearing mice.
  • the testing articles were administrated to the mice according to the predetermined regimen as shown in the experimental design table (Tables E18) .
  • Table E18 Description of experimental design for in vivo NCI-H1373 xenograft models
  • QD daily a.
  • N number of animals per group;
  • Dosing volume adjust dosing volume based on body weight 10 ⁇ L/g; If body weight loss >15%, treatment will be suspended until body weight loss ⁇ 10%;
  • the experiment’s duration was 168 days.
  • d The entire study period consisted of 3 phases.
  • Monotherapy phase treatment with single agent of Compound 17 and MRTX849 until tumor relapse.
  • Monotherapy-R treatment switched to 100 mg/kg Compound 17 after relapse from monotherapy phase.
  • Combination-R treatment switched to Compound 17 and WX001 after relapse from monotherapy-R phase. Tumor relapse was defined as mean TV that rebounded from regressions to 500 mm 3 .
  • TGI Tumor Growth Inhibition
  • KRAS G12C inhibitors including MRTX849 and Compound 17 in NCI-H1373 human lung cancer xenograft model (aKRAS G12C inhibitor sensitive model) was investigated (monotherapy phase) .
  • aKRAS G12C inhibitor sensitive model the potential of Compound 17 as a single agent or in combination with WX001 to overcome MRTX849 acquired resistance was evaluated (monotherapy-R and combination-R phase, respectively) .
  • FIG. 18 Body weight change during the monotherapy phase of the experiment is shown in FIG. 18. Because tumor volume exceeded 3,000 mm 3 , mice in vehicle group were sacrificed during the monotherapy phase. Because of bad health condition, one mouse in group 3 was sacrificed during the monotherapy phase.
  • FIG. 19 Body weight change during the monotherapy-R and combination-R phase of the experiment is shown in FIG. 19.
  • the monotherapy-R phase all mice in Group 3 were well tolerated to up to 100 mg/kg Compound 17 single agent treatment.
  • the combination-R phase all mice in Group 3 were well tolerated to Compound 17 + WX001, 30 mg/kg + 50 mg/kg.

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Abstract

La présente invention concerne des thérapies (par ex., polythérapies) pour traiter des cancers avec un inhibiteur d'ERK1/2 et/ou un inhibiteur de KRAS G12C. Dans certains cas, le cancer est résistant (par ex., résistance acquise) à un inhibiteur de KRAS G12C. Dans certains cas, l'inhibiteur d'ERK 1/2 est WX001. Dans certains modes de réalisation, l'inhibiteur de KRAS G12C est le composé 17.
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