| Project/Area Number |
16H05433
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory surgery
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| Research Institution | Kindai University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
西尾 和人 近畿大学, 医学部, 教授 (10208134)
冨田 秀太 岡山大学, 医歯薬学総合研究科, 准教授 (10372111)
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| Research Collaborator |
SUDA Kenichi
KOBAYASHI Yoshihisa
KOGA Takamasa
FUJINO Toshio
NISHINO Masaya
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2016: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
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| Keywords | 肺癌 / 分子標的治療 / ドライバー癌遺伝子 / チロシンキナーゼ / MET / エクソン14スキッピング / 肺がん / MET遺伝子 / チロシンキナーゼ阻害剤 / 獲得耐性 / ENU / EGFR遺伝子 |
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| Outline of Final Research Achievements |
We established a Ba/F3 cell model with MET exon 14 skipping mutation that is present about3% of lung adenocarcinoma . Using this model, we tested its sensitivities to 8 MET-tyrosine kinase inhibitors (TKI) including 4 type I TKI that binds to the active form of the kinase, 3 type II that binds to the inactive form and one allosteric inhibitor. As a result, capmatinib was found to be most effective. Next, we derived resistant clones for each drug. D1228 and Y1230 were common sites of the secondary MET mutations for resistant cells against type I TKI, whereas L1195 and F1200 were common sites for the type II TKI. In general, the resistance mutation for type I is sensitive to type II, and vice versa.
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| Academic Significance and Societal Importance of the Research Achievements |
現在わが国ではEGFR(50%), ALK(3％), ROS1(2%), BRAF(1%)の4種の遺伝子異常有する肺癌の分子標的治療が可能である。最近、新規のドライバーとしてMET遺伝子のエクソン14スキッピング変異が注目されているが、最適な薬剤の検討、耐性機序の解析については十分ではない。本研究ではこの変異の細胞モデルを作成し、8種のMET阻害剤の活性の比較、耐性機序の解析を行った。この結果は将来の肺癌治療の基礎データとして国民に還元し得るものである。
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