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WO2006041036A1 - Procédé permettant d’estimer ou de juger de l’efficacité de l’effet antitumoral d’un inhibiteur de kinase tyrosine de récepteur de facteur de croissance épidermique - Google Patents

Procédé permettant d’estimer ou de juger de l’efficacité de l’effet antitumoral d’un inhibiteur de kinase tyrosine de récepteur de facteur de croissance épidermique Download PDF

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Publication number
WO2006041036A1
WO2006041036A1 PCT/JP2005/018651 JP2005018651W WO2006041036A1 WO 2006041036 A1 WO2006041036 A1 WO 2006041036A1 JP 2005018651 W JP2005018651 W JP 2005018651W WO 2006041036 A1 WO2006041036 A1 WO 2006041036A1
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WO
WIPO (PCT)
Prior art keywords
primer set
lung cancer
growth factor
factor receptor
epidermal growth
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PCT/JP2005/018651
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English (en)
Japanese (ja)
Inventor
Hiromi Wada
Fumihiro Tanaka
Makoto Sonobe
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Kyoto University NUC
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Kyoto University NUC
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Publication of WO2006041036A1 publication Critical patent/WO2006041036A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to a method for rapidly and accurately predicting or diagnosing an antitumor effect by a tyrosine kinase inhibitor of an epidermal growth factor receptor such as gefitib.
  • the present invention also relates to a kit used for carrying out the prediction or diagnosis method.
  • EGFR epidermal growth factor receptor
  • an anti-tumor agent targeting EGFR has been marketed in Japan since 2002 as a drug expected to have a high anti-tumor effect against non-small cell lung cancer for which conventional chemotherapy is ineffective Has been.
  • Gefitinib is effective for 10 to 30% of patients with non-small cell lung cancer, but it does not show anti-tumor effects in other patients, but only about 7% of patients have acute lung injury. It can be said that fatal side effects such as these are caused.
  • Non-Patent Document 1 Sachiko Sugai, “Gene Diagnosis of Cancer”, Tokyo Metropolitan Society, Vol.31, No.l, p.12-1 6
  • An object of the present invention is to solve the above-described problems of the prior art. Specifically, the present invention provides a rapid and accurate detection of mutations in exons 18, 19 and 21 of the EGFR gene from a small amount of specimen, thereby rapidly and accurately improving the antitumor effect of EGFR tyrosine kinase inhibitors such as Geifib. The purpose is to provide a technology for predicting.
  • the present inventors have found a primer particularly suitable for detecting mutations in exons 18, 19 and 21 of the EGFR gene by the PCR-SSCP method.
  • the PCR-SSCP method is used to detect the EGFR gene exons 18, 19 and 21 mutations at a detection rate of 100% or close even when a formalin-fixed sample is used as the sample. It was confirmed that the antitumor effect of gefitiv can be predicted quickly and accurately based on the presence or absence of the detection of the gene mutation.
  • the present invention has been completed by further studies based on the strong knowledge.
  • the present invention is the following inventions:
  • Item 1 A method for predicting or diagnosing the effectiveness of an antitumor effect against non-small cell lung cancer by a tyrosine kinase inhibitor of an epidermal growth factor receptor, comprising the following steps:
  • Non-small cell lung cancer patient power Epithelial growth factor receptor remains in collected lung cancer tissue pieces At least one of the partial sequences of exons 18, 19, and 21 of the gene is amplified by PCR using at least one primer set selected from the primer sets (a) to (e) below The process of
  • step (1) using the primer set (a) or (b), the primer set (c), and the primer set (d) or (e), an exon of the epidermal growth factor receptor gene Item 18.
  • step (1) using the primer set (a), the primer set (c), and the primer set (e), the epidermal growth factor receptor gene exons 18, 19, and 21 Item 3.
  • Item 4. The prediction or diagnosis method according to any one of Items 1 to 3, wherein the lung cancer tissue fragment from which the lung cancer patient power was also collected is fixed in formalin.
  • Item 5 The prediction or diagnosis method according to any one of Items 1 to 4, wherein the tyrosine kinase inhibitor of the epidermal growth factor receptor is Getivib.
  • Item 6 Effectiveness of antitumor effect against non-small cell lung cancer by a tyrosine kinase inhibitor of epidermal growth factor receptor containing at least one primer set selected from the primer sets of (a) to (e) below: Kit for prediction or diagnosis:
  • FIG. 1 Electrophoresis by PCR-SSCP obtained in Example 1 using a frozen specimen of lung cancer tissue specimen as a specimen and using the primer set of (a) or (b) Is the result of
  • FIG. 2 shows the result of electrophoresis by PCR-SSCP method obtained using the primer set of (c) using a frozen specimen of lung cancer tissue as a specimen in Example 1.
  • FIG. 3 shows the results of electrophoresis by PCR-SSCP obtained in Example 1 using a frozen specimen of lung cancer tissue specimen as a specimen and using a set of primers (d) or (e).
  • FIG. 4 shows the results of electrophoresis using the PCR-SSCP method obtained with the primer set (c) using a frozen specimen of lung cancer tissue and a formalin-fixed specimen as samples in Example 2. .
  • the present invention is a method for predicting or diagnosing the effectiveness of an anti-tumor effect of a tyrosine kinase inhibitor of EGFR against non-small cell lung cancer.
  • the tyrosin kinase inhibitor is not particularly limited, and examples thereof include gefitinib and eroticin.
  • gefitiv is a molecularly targeted anticancer agent used for the treatment of advanced non-small cell lung cancer that has been effective with other therapies, and the method of the present invention is non-small cell of gefitib. Suitable for predicting the effectiveness of antitumor effects on lung cancer
  • Gefitiv is marketed by AstraZeneca under the trade name “Iressa”.
  • the cancer for which the antitumor effect is judged to be effective is non-small cell lung cancer, but is preferably progressive non-small cell lung cancer.
  • step (1) At least one of the partial sequences of exon 18, 19, and 21 of the epidermal growth factor receptor gene contained in a lung cancer tissue sample collected from non-small cell lung cancer patients is identified. Amplify by PCR using the primer set (step (1)).
  • Non-small cell lung cancer patient force The method of collecting a lung cancer tissue fragment is not particularly limited, and examples thereof include methods commonly practiced clinically such as bronchoscopic biopsy and percutaneous biopsy. Is done.
  • the lung cancer tissue piece may be a mixture of cancer cells and normal cells.
  • the collected lung cancer tissue piece may be used in this step (1) as it is, but a formalin-fixed one or a cryopreserved one may be used.
  • a formalin-fixed lung cancer tissue fragment is advantageous in that it can be used in the past.
  • a lung cancer tissue piece is subjected to DNA extraction treatment to prepare genomic DNA derived from the lung cancer tissue piece.
  • the DNA extraction treatment can be performed by a method well known in the technical field of the present invention.
  • a commercially available DNA extraction kit such as Fast DNA kit (manufactured by Qbiogene Inc.) can also be used.
  • the target partial sequence can be amplified even with a very small amount of DNA. For example, even if one abnormal gene is mixed in 1 million normal genes, the abnormal gene can be amplified and detected.
  • the obtained genomic DNA as a saddle type, using at least one primer set selected from the primer sets (a) to (e) below, the EGFR gene exon 18, 1 Amplify at least one of the 9 and 21 subsequences.
  • the partial sequence (219 bp) of exon 18 of the normal EGFR gene can be amplified with the primer set (a) above.
  • the partial sequence (169 bp) of exon 18 of the normal EGFR gene can be amplified by the primer set (b).
  • the partial sequence (239 bp) of exon 19 of the normal EGFR gene can be amplified by the primer set (c).
  • the partial sequence (222bp) of exon 21 of the normal EGFR gene can be amplified with the primer set of (a) and the partial sequence (154bp) of exon 21 of the normal EGFR gene can be amplified with the primer set of (e). it can.
  • the primer set (a) or (b) is used to detect the mutation of exon 18, the primer set (c) is used to detect the mutation of etason 19, and the mutation of exon 21 For detection of (d) or (e), the primer set is used.
  • the EGFR gene exons 18, 19, and 21 It is desirable to confirm the presence or absence of mutations in all. Therefore, in this step, using the primer set (a) or (b), the primer set (c), and the primer set (d) or (e), respectively, the exon of the epidermal growth factor receptor gene 18 , 19 and 21 are preferably amplified by the PCR method, respectively.
  • the primer set (a) and the ply (c) It is desirable to amplify the partial sequences of exon 18, 19 and 21 of the epidermal growth factor receptor gene by PCR using the primer set of Mercer and the primer set of (e), respectively.
  • PCR conditions are not particularly limited, and can be set as appropriate according to the apparatus to be used.
  • one cycle force including heat denaturation of DNA strands, annealing of primers and synthesis of complementary strands by polymerase, for example, is repeated 10 to 50 times, preferably 20 to 40 times.
  • the amplified product obtained in the above step (1) is analyzed by the SSCP method (single-stranded DNA higher-order structure polymorphism analysis method) to confirm the presence or absence of mutations in the partial sequence (step ( 2)).
  • SSCP method single-stranded DNA higher-order structure polymorphism analysis method
  • the mobility of electrophoresis in the amplification product obtained from the EGFR gene strength derived from lung cancer tissue fragments is compared with the mobility of electrophoresis in the amplification product obtained using the normal EGFR gene as a saddle type. It is confirmed by this. Visualization of the band of the amplified amplification product can be performed according to a method known in the art.
  • the SSCP conditions in step (2) are not particularly limited as long as it is possible to identify the presence or absence of mutations in the amplification product obtained in step (1) above.
  • the following conditions are exemplified.
  • Electrophoresis conditions Normal 10-20W
  • Electrophoresis time Usually 60 to 180 minutes, preferably 60 to 90 minutes
  • step (3) the effectiveness of the antitumor effect of gemifib against the lung cancer patient is predicted (step (3)).
  • the tyrosine kinase inhibitor of EGFR has an antitumor effect effectively against non-small cell lung cancer Demonstrating the power to demonstrate.
  • the mutation detected by using the primer set of (a) or (b) corresponds to a mutation on exon 18 of the EGFR gene.
  • the mutation detected by using the primer set (C) corresponds to the mutation on exon 19 of the EGFR gene.
  • the mutation detected by using the primer set (d) or (e) corresponds to the mutation on exon 21 of the EGFR gene.
  • the primer sets (a) to (e) are used in a method for predicting or diagnosing the effectiveness of an anti-tumor effect of a tyrosine kinase inhibitor of EGFR against non-small cell lung cancer. Therefore, the present invention further relates to non-small cell lung cancer caused by an epidermal growth factor receptor tyrosine kinase inhibitor containing at least one primer set selected from the primer sets (a) to (e).
  • the kit should contain reagents necessary for PCR and reagents required for the SSCP method.
  • the primer sets (a) and (b) are particularly suitable for detecting the mutation of exon 18 of the EGFR gene by PCR-SSCP method.
  • the primer set (c) is particularly suitable for detecting the mutation of EGFR gene exon 19 by PCR-SSCP method.
  • the primer sets (d) and (e) are particularly suitable for detecting the mutation of exon 21 of the EGFR gene by PCR-SSCP method. Therefore, the present invention further provides the following inventions (1) to (3):
  • ⁇ is an anti-primer
  • FIG. 1 shows an example of the results (electrophorogram) obtained when primer sets (a) and (b) were used in this example.
  • lanes 1, 2, 4, and 5 are not mutated! ⁇ Lung cancer tissue fragment with the EGFR gene; and lane 3 is the EGFR gene with G at position 2155 replaced with A This is a result of testing a lung cancer tissue piece.
  • FIG. 2 shows an example of the results (electrophoretic diagram) obtained when the primer set (c) was used in this example.
  • lane 1 is the EGFR gene at the 2240th position, the 2257th position, the nucleotide at position 2257 is deleted, and a lung cancer tissue fragment having a mutation; lanes 2-4 and 6 are mutated, the EGFR gene
  • Lane 5 is a lung cancer tissue fragment having a mutation in which nucleotides 2235 to 2249 are deleted;
  • lane 7 is an EG This is the result of testing a lung cancer tissue fragment having a mutation in which the nucleotide at position 2236 of FR gene has been deleted.
  • FIG. 3 shows an example of the results (electrophoresis diagram) obtained when the primer sets (a) and (b) were used in this example.
  • lanes 1, 2, 4 and 5 are not mutated! ⁇ Lung cancer tissue fragment with EGFR gene; and lane 3 is the EGFR gene with the T at position 2573 replaced with G This is a result of testing a lung cancer tissue piece.
  • Primer sets (i) to (xi) shown in Table 2 can be cited as candidates for the primer sets used for the amplification of EGFR gene exons 18, 19, and 21. Therefore, except that these primer sets (i) to (xi) were used, the presence or absence of mutations in exons 18, 19, and 21 of the EGFR gene derived from lung cancer tissue fragments was confirmed in the same manner as in Example 1 above. did.
  • Non-small cell lung cancer patients with mutations in EGFR gene exon 19 Lung cancer tissue pieces were collected. Divided into two, one was frozen and the other was formalin-fixed.
  • lung cancer tissue fragments were collected from non-small cell lung cancer patients with no mutation in the EGFR gene. Divided into two, one was frozen and the other was formalin-fixed.
  • E derived from a lung cancer tissue fragment was prepared in the same manner as in the above example. The presence or absence of mutations in exons 18, 19 and 21 of the GFR gene was confirmed.
  • FIG. 2 shows an (electrophoretic diagram) obtained when the primer set (c) was used in this example. In the electrophoresis photograph of Fig.
  • lane 1 has no mutation in the EGFR gene and frozen specimen of lung cancer tissue piece;
  • lane 2 is a frozen specimen of lung cancer tissue piece in which mutation is found in EGFR gene exon 19;
  • lane 3 is the formalin-fixed specimen of a lung cancer tissue piece with no mutation in the EGFR gene;
  • lane 4 is the test result of a formalin-fixed specimen of a lung cancer tissue piece in which mutation is found in the EGFR gene exon 19.
  • the primer primer used in the PCR-SSCP method is designed to detect EGFR gene mutation with an accuracy of 100% or near that is impossible with the normal PCR-SS CP method. Therefore, it is possible to predict the antitumor effect of an EGFR tyrosine kinase inhibitor on non-small cell lung cancer patients with extremely high accuracy.
  • a formalin-fixed sample can also be used as a sample. Therefore, it is possible to predict the antitumor effect of an EGFR tyrosine kinase inhibitor using samples collected in the past, and the physical burden on patients can be reduced.
  • many patients who receive EGFR tyrosine kinase inhibitors are end-stage cancers, and it is often difficult to collect new specimens in order to search for EGFR gene mutations.
  • this diagnostic method which can predict the effects of EGFR tyrosine kinase inhibitors using samples collected in the past, is a gospel for many cancer patients.

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Abstract

L’invention concerne une technique pour estimer rapidement et avec précision l’effet antitumoral d’un inhibiteur de kinase tyrosine EGFR comme le Gefitinib en détectant rapidement et avec précision la mutation dans les exons 18, 19 et 21 d’un gène EGFR à partir d’un spécimen dans une quantité mineure. A l’aide des ensembles initiateurs (a) à (e) selon le procédé PCR-SSCP, on détecte les exons 18, 19 et 21 d’un gène EGFR. On détecte ainsi la présence ou l’absence de mutation dans le gène avec une précision de 100% ou proche de 100%. On estime alors sur la base de la présence ou de l’absence de mutation génétique, l’effet antitumoral du Gefitinib.
PCT/JP2005/018651 2004-10-08 2005-10-07 Procédé permettant d’estimer ou de juger de l’efficacité de l’effet antitumoral d’un inhibiteur de kinase tyrosine de récepteur de facteur de croissance épidermique Ceased WO2006041036A1 (fr)

Applications Claiming Priority (2)

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JP2004296559A JP2008005701A (ja) 2004-10-08 2004-10-08 上皮増殖因子受容体のチロシンキナーゼ阻害剤の抗腫瘍効果の有効性の予測診断方法
JP2004-296559 2004-10-08

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1988164A4 (fr) * 2006-02-23 2009-04-22 Univ Kanazawa Nat Univ Corp Procédé destiné à tester la sensibilité d'un cancer solide contre un inhibiteur de tyrosine kinase et nécessaire de test correspondant
CN107653303A (zh) * 2017-10-11 2018-02-02 广州立菲达安诊断产品技术有限公司 一种用于检测egfr基因突变的扩增引物、测序引物、试剂盒和方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE NUCLEOTIDE [online] 26 January 2001 (2001-01-26), ULRICH A ET AL: "Homo sapiens epidermal growth factor receptor (EGFR) gene, complete cds, alternatively spliced; and 5S ribosomal RNA gene.", XP002999207, accession no. ncbi Database accession no. (AF288738) *
LYNCH T J ET AL: "Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.", THE NEW ENGLAND JOURNAL OF MEDICINE., vol. 350, no. 21, 20 May 2004 (2004-05-20), pages 2129 - 2139, XP002359960 *
PAEZ J G ET AL: "EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.", SCIENCE., vol. 304, no. 5676, 4 June 2004 (2004-06-04), pages 1497 - 1500, XP002359959 *
YODOSHA.: "Bio Manual UP Series PCR-Ho no Saishin Gijutsu.", EXPERIMENTAL MEDICINE SEPARATE VOLUME., 5 February 1995 (1995-02-05), pages 33 - 43, XP002999208 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1988164A4 (fr) * 2006-02-23 2009-04-22 Univ Kanazawa Nat Univ Corp Procédé destiné à tester la sensibilité d'un cancer solide contre un inhibiteur de tyrosine kinase et nécessaire de test correspondant
CN107653303A (zh) * 2017-10-11 2018-02-02 广州立菲达安诊断产品技术有限公司 一种用于检测egfr基因突变的扩增引物、测序引物、试剂盒和方法

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