Molecular targeted therapy against adenocarcinoma of the lung harboring MET exon 14 skipping mutation

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H05433
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory surgery
• Research Institution: Kindai University
• Principal Investigator: MITSUDOMI Tetsuya 近畿大学, 医学部, 教授 (70209807)
• 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)
• Research Collaborator: SUDA Kenichi ; KOBAYASHI Yoshihisa ; KOGA Takamasa ; FUJINO Toshio ; NISHINO Masaya
• Project Period (FY): 2016-04-01 – 2019-03-31
• 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

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.

Free Research Field

呼吸器外科学

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。