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

• 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
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥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)
• 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

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.

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。

Research Products

• [Journal Article] EGFR T790M and C797S Mutations as Mechanisms of Acquired Resistance to Dacomitinib (2018)
  • Author(s): Kobayashi Y, Fujino T, Nishino M, Koga T, Chiba M, Sesumi Y, Ohara S, Shimoji M, Tomizawa K, Takemoto T, Mitsudomi T
  • Journal Title: Journal of Thoracic Oncology Volume: ePub中 Issue: 5 Pages: 727-731
  • DOI: 10.1016/j.jtho.2018.01.009
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Efficacy of irreversible EGFR-TKIs for the uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A. (2017)
  • Author(s): Chiba M, Togashi Y, Bannno E, Kobayashi Y, Nakamura Y, Hayashi H, Terashima M, De Velasco MA, Sakai K, Fujita Y, Mitsudomi T, Nishio K.
  • Journal Title: BMC Cancer. Volume: 17 Issue: 1 Pages: 281-281
  • DOI: 10.1186/s12885-017-3263-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of dasatinib on EMT-mediated-mechanism of resistance against EGFR inhibitors in lung cancer cells. (2017)
  • Author(s): Sesumi Y, Suda K, Mizuuchi H, Kobayashi Y, Sato K, Chiba M, Shimoji M, Tomizawa K, Takemoto T, Mitsudomi T.
  • Journal Title: Lung Cancer Volume: 104 Pages: 85-90
  • DOI: 10.1016/j.lungcan.2016.12.012
  • Peer Reviewed
• [Journal Article] Characterization of EGFR T790M, L792F, and C797S Mutations as Mechanisms of Acquired Resistance to Afatinib in Lung Cancer. (2017)
  • Author(s): Kobayashi Y, Azuma K, Nagai H, Kim YH, Togashi Y, Sesumi Y, Chiba M, Shimoji M, Sato K, Tomizawa K, Takemoto T, Nishio K, Mitsudomi T
  • Journal Title: Mol Cancer Ther. Volume: 16 Issue: 2 Pages: 357-364
  • DOI: 10.1158/1535-7163.mct-16-0407
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] In Vitro Evaluation for Optimal MET-TKI Selection in Lung Cancers with MET Mutations Including Exon 14 Skipping. (2018)
  • Author(s): Fujino T, Suda K, Kobayashi Y, Nishino M, Koga T, Ohara S, Chiba M, Shimoji M, Takemoto T, MItsudomi T.
  • Organizer: 19th World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] アファチニブ獲得耐性機序としてのEGFR二次変異T790M, L792F, C797Sの特徴 (2016)
  • Author(s): 小林祥久、光冨徹哉ら
  • Organizer: 第57回日本肺癌学会
  • Place of Presentation: 福岡国際会議場（福岡市）
  • Year and Date: 2016-12-19
• [Presentation] まれなEGFR遺伝子の耐性二次変異における各種EGFR-TKI感受性 (2016)
  • Author(s): 千葉眞人、光冨徹哉ら
  • Organizer: 第57回日本肺癌学会
  • Place of Presentation: 福岡国際会議場（福岡市）
  • Year and Date: 2016-12-19
• [Presentation] EGFR T790M, L792F, and C797S Mutations as Mechanisms of Acquired Resistance to Afatinib (2016)
  • Author(s): Kobayashi, Y., and Mitsudomi, T., et al.
  • Organizer: World Conference of Lung Cancer
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2016-12-04
  • Int'l Joint Research
• [Presentation] Effect of dasatinib on EMT-mediated mechanism of resistance against EGFR inhibitors in lung cancer cells (2016)
  • Author(s): Sesumi, Y., and Mitsudomi, T., et al.
  • Organizer: World Conference of Lung Cancer
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2016-12-04
  • Int'l Joint Research
• [Presentation] Dasatinib prevents EMT-mediated acquired resistance to EGFR-TKls in a mutant NSCLC cell line (2016)
  • Author(s): Sesumi, Y., and Mitsudomi, T., et al.
  • Organizer: 第75回日本癌学会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Sequential EGFR-TKI strategy to overcome acquired resistance to afatinib: novel secondary mutations L792F and C797S in addition to T790M (2016)
  • Author(s): Sesumi, Y., and Mitsudomi, T., et al.
  • Organizer: Asia Pcific Lung Cancer Conference
  • Place of Presentation: Chiang-Mai, Thailand
  • Year and Date: 2016-05-13
  • Int'l Joint Research