Development of new treatment strategy for lung cancer haboring MET exon14 mutation

• Project/Area Number: 19K16813
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Kindai University
• Principal Investigator: Fujino Toshio 近畿大学, 医学部, 助教 (90813981)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 非小細胞肺癌 / 分子標的治療 / MET遺伝子変異 / 獲得耐性変異 / MET exon14 skipping変異 / MET-TKI / 耐性二次変異 / 初期耐性 / 獲得耐性 / 二次変異 / MET exon 14遺伝子変異 / チロシンキナーゼ阻害剤 / 耐性機序

Outline of Research at the Start

MET exon14遺伝子変異は、非小細胞肺癌の3-4%程度に認められるドライバー遺伝子変異であり、EGFR遺伝子変異やALK、ROS1融合遺伝子に続く新規治療ターゲットとして注目されている。METチロシンキナーゼ阻害剤を用いた複数の臨床試験が進行中であるが、すでにこれら薬剤に対する耐性変異の出現が報告されており、他のチロシンキナーゼ阻害剤治療と同様に耐性機序の同定・克服が今後の課題になると予測される。
本研究では、MET exon14遺伝変異を有する人工腫瘍細胞モデルを用いてMETチロシンキナーゼ阻害剤の耐性機序の網羅的な解析とその克服方法を明らかにすることでMET exon14遺伝変異陽性肺癌の治療戦略を確立することを目的とする。

Outline of Final Research Achievements

Two MET-TKIs (capatinib and tepotinib) were approved in 2020 for use in non-small cell lung cancer with MET exon14 skipping mutation. However, there is a problem that some patients show primary resistance to these drugs and that even responders will eventually develop resistance to these drugs.
We have shown that foretinib may be useful for overcoming on-target resistance mutations to capatinib and tepotinib. We also found that heterogeneity of cancer-related genes besides MET gene may influence the efficacy of MET-TKI.

Academic Significance and Societal Importance of the Research Achievements

本研究で得られた知見により、MET exon14 skipping変異を伴う肺癌患者において、初回に投与されたMET阻害剤に耐性を来した場合でも、再び有効な治療を受ける機会が提供できる可能性がある。

Research Products

• [Journal Article] Intra-tumor and Inter-tumor Heterogeneity in MET Exon 14 Skipping Mutations and Co-mutations in Pulmonary Pleomorphic Carcinomas (2021)
  • Author(s): Fujino Toshio、Suda Kenichi、Sakai Kazuko、Murakami Isao、Shimizu Shigeki、Ohara Shuta、Koga Takamasa、Hamada Akira、Soh Junichi、Nishio Kazuto、Mitsudomi Tetsuya
  • Journal Title: Clinical Lung Cancer Volume: - Issue: 3 Pages: e185-e195
  • DOI: 10.1016/j.cllc.2021.09.005
  • Peer Reviewed
• [Journal Article] Acquired Resistance Mechanism for MET Tyrosine Kinase Inhibitor (2021)
  • Author(s): Fujino Toshio、Mitsudomi Tetsuya
  • Journal Title: JTO Clinical and Research Reports Volume: 2 Issue: 3 Pages: 100134-100134
  • DOI: 10.1016/j.jtocrr.2020.100134
  • Open Access
• [Journal Article] Lung Cancer with MET exon 14 Skipping Mutation: Genetic Feature, Current Treatments, and Future Challenges. (2021)
  • Author(s): Fujino T, Suda K, Mitsudomi T.
  • Journal Title: Lung Cancer: Targets and Therapy Volume: 12 Pages: 35-50
  • DOI: 10.2147/lctt.s269307
  • Peer Reviewed / Open Access
• [Journal Article] Emerging MET tyrosine kinase inhibitors for the treatment of non-small cell lung cancer (2020)
  • Author(s): Fujino T, Suda K, Mitsudomi T
  • Journal Title: Expert Opinion on Emerging Drugs Volume: 25 Issue: 3 Pages: 229-249
  • DOI: 10.1080/14728214.2020.1791821
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Treatment strategy of lung cancer with MET, NTRK and BRAF gene aberrations: Insights from in vitro and clinical data (2022)
  • Author(s): Toshio Fujino, Kenichi Suda and Tetsuya Mitsudomi
  • Organizer: 2022 the Japanese Society of Medical Oncology Annual Meeting
  • Invited
• [Presentation] Dysregulation of MET: its significance in carcinogenesis and treatment of lung cancer (2021)
  • Author(s): Toshio Fujino, Kenichi Suda and Tetsuya Mitsudomi
  • Organizer: The 62nd Annual Meeting of the Japan Lung Cancer Society
  • Invited
• [Presentation] MET exon 14 skipping変異肺癌におけるType I MET-TKI耐性二次的変異とその克服 (2021)
  • Author(s): 藤野智大、須田健一、小原秀太、濱田顕、千葉眞人、 下治正樹、武本智樹、宗淳一、光冨徹哉
  • Organizer: 第62回日本肺癌学会学術集会
• [Presentation] MET exon14 skipping変異陽性肺多形癌における intra-およびinter-tumor heterogeneityの検討 (2021)
  • Author(s): 藤野智大、須田 健一、坂井和子、清水重喜 、村上功、小原秀太、古賀教将、 西野将矢、濱田顕、千葉眞人、武本智樹、宗淳一、西尾和人、光冨徹哉
  • Organizer: 第121回 日本外科学会定期学術集会
• [Presentation] MET遺伝子変異陽性肺癌の病態と MET-TKIに対する感受性と耐性機序 (2020)
  • Author(s): 藤野智大
  • Organizer: 第61回 日本肺癌学会
  • Invited
• [Presentation] Comprehensive analysis of secondary mutation as resistance mechanism to seven MET-TKIs for MET exon 14 skipping in vitro (2019)
  • Author(s): Toshio Fujino
  • Organizer: 20th World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] MET exon14 skipping変異陽性多形癌におけるInter-tumor Heterogeneityの検討 (2019)
  • Author(s): 藤野 智大
  • Organizer: 第60回日本肺癌学会学術集会
• [Book] 呼吸器ジャーナル (2020)
  • Author(s): 藤野 智大, 須田 健一, 光冨 徹哉
  • Total Pages: 8
  • Publisher: 医学書院
  • ISBN: 4260029029
• [Patent(Industrial Property Rights)] タイプＩ型抗がん剤に耐性を獲得した肺癌用治療薬 (2021)
  • Inventor(s): 藤野智大、光冨徹哉
  • Industrial Property Rights Holder: 藤野智大、光冨徹哉
  • Industrial Property Rights Type: 特許
  • Filing Date: 2021
  • Overseas
• [Patent(Industrial Property Rights)] タイプI型抗がん剤に耐性を獲得した肺癌用治療薬 (2021)
  • Inventor(s): 藤野智大、光冨徹哉
  • Industrial Property Rights Holder: 藤野智大、光冨徹哉
  • Industrial Property Rights Type: 特許
  • Filing Date: 2021
  • Overseas