Development of a new treatment strategy for HER2-alterated lung cancer

• Project/Area Number: 19K09285
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55040:Respiratory surgery-related
• Research Institution: Kindai University
• Principal Investigator: Soh Junichi 近畿大学, 医学部, 教授 (90559890)
• Co-Investigator(Kenkyū-buntansha): 冨田 秀太 岡山大学, 大学病院, 准教授 (10372111) ; 豊岡 伸一 岡山大学, 医歯薬学総合研究科, 教授 (30397880) ; 山本 寛斉 岡山大学, 大学病院, 講師 (40467733) ; 阪口 政清 岡山大学, 医歯薬学総合研究科, 教授 (70379840) ; 光冨 徹哉 近畿大学, 医学部, 教授 (70209807) ; 須田 健一 近畿大学, 医学部, 講師 (30631593) ; 諏澤 憲 岡山大学, 大学病院, 助教 (90839713)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: HER2 / 肺癌 / 薬剤耐性 / ERBB2 / HER2異常 / 肺がん / 乳がん / 胃がん / HER異常

Outline of Research at the Start

がん遺伝子HER2が活性化している乳がん・胃がんに対してHER2標的療法が保険収載されています。HER2異常を有する肺がんにおける頻度は5%程度であり、年間約8万人の肺がん死亡者数のうち4000人程度にHER2異常が存在する可能性があります。HER2異常肺がんへのHER2標的療法は、先行研究でその有効性が示唆されていますが、肺がんに対するHER2標的療法は適応外であり、対策が遅れています。本研究では、HER2異常肺がんへのHER2標的療法の効果とその獲得耐性の克服を検討することで、HER2異常肺がんに対するプレシジョン・メディシンの確立を目指した基礎的検討を実施します。

Outline of Final Research Achievements

We conducted sensitivity testing and investigated the mechanism of acquired resistance using lung, gastric, and breast cancer cell lines for several HER2-targeting agents, and reported the results in several English papers. In addition, we confirmed the sensitivity of a novel HER inhibitor, Tarloxotinib, and identified a new resistance-related mutation, HER2 exon C805S, involved in resistance using Ba/F3 cells transfected with HER2 mutation, which was reported in an English paper. A new afatinib-sensitive HER2 mutation spectrum identified in the LUX-Lung8 study, which evaluated the efficacy of the EGFR/HER2 inhibitor afatinib in patients with squamous cell lung cancer, was introduced into the Ba/F3 cell line and its pathogenicity and drug sensitivity were investigated and reported in an English paper.

Academic Significance and Societal Importance of the Research Achievements

HER2異常肺癌の頻度は5%程度であるが、HER2異常は複数の癌腫で認められ、HER2標的療法は個別化治療として期待される。HER2異常スペクトル別にHER2標的薬の効果とその獲得耐性の克服を検討することで、HER2異常肺癌に対するプレシジョン・メディシンの確立を目指した基礎的検討を実施した。HER2異常細胞株を用いて、複数のHER2標的薬の効果を検討し、長期暴露による薬剤耐性株や人工的なHER2変異導入細胞株の樹立により、耐性機序の解明とその治療法の開発を行い、複数の報告を行っている。

Research Products

• [Journal Article] In vitro validation study of HER2 and HER4 mutations identified in an ad hoc secondary analysis of the LUX-Lung 8 randomized clinical trial. (2021)
  • Author(s): Hamada A, Suda K, Koga T, Fujino T, Nishino M, Ohara S, Chiba M, Shimoji M, Takemoto T, Soh J, Uchida T, Mitsudomi T.
  • Journal Title: Lung Cancer Volume: 162 Pages: 79-85
  • DOI: 10.1016/j.lungcan.2021.10.014
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Activity and mechanism of acquired resistance to tarloxotinib in HER2 mutant lung cancer: an in vitro study. (2021)
  • Author(s): Koga T, Suda K, Nishino M, Fujino T, Ohara S, Hamada A, Soh J, Tirunagaru V, Vellanki A, Doebele RC, Mitsudomi T.
  • Journal Title: Translational Lung Cancer Research Volume: 10 Issue: 8 Pages: 3659-3670
  • DOI: 10.21037/tlcr-21-216
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] YES1 activation induces acquired resistance to neratinib in HER2 ‐amplified breast and lung cancers (2020)
  • Author(s): Takeda Tatsuaki、Yamamoto Hiromasa、Suzawa Ken、Tomida Shuta、Miyauchi Shunsaku、Araki Kota、Nakata Kentaro、Miura Akihiro、Namba Kei、Shien Kazuhiko、Soh Junichi、Shien Tadahiko、Kitamura Yoshihisa、Sendo Toshiaki、Toyooka Shinichi
  • Journal Title: Cancer Science Volume: 111 Issue: 3 Pages: 849-856
  • DOI: 10.1111/cas.14289
  • NAID: 120006839439
  • Peer Reviewed / Open Access
• [Journal Article] Acquired resistance mechanisms to afatinib in HER2-amplified gastric cancer cells (2019)
  • Author(s): Yoshioka, T. Shien, K. Takeda, T. Takahashi, Y. Kurihara, E. Ogoshi, Y. Namba, K. Torigoe, H. Sato, H. Tomida, S. Yamamoto, H. Soh, J. Fujiwara, T. Toyooka, S.
  • Journal Title: Cancer Sci Volume: 110 Issue: 8 Pages: 2549-2557
  • DOI: 10.1111/cas.14089
  • NAID: 120006816640
  • Peer Reviewed / Open Access
• [Presentation] In Vitro Validation Study for HER2 Mutations in Squamous Cell Carcinoma as a Potential Predictive Factor Identified in Secondary Analysis of the LUX-Lung 8 Trial (2020)
  • Author(s): Akira Hamada, Kenichi Suda, Toshio Fujino, Masaya Nishino, Takamasa Koga, Shuta Ohara, Masato Chiba, Toshiki Takemoto, Junichi Soh, Tetsuya Mitsudomi
  • Organizer: 2020 World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] In Vitro Validation Study for Afatinib Efficacy in Lung Squamous Cell Carcinoma with HER2 Mutations Identified in LUX-Lung 8 Trial (2020)
  • Author(s): Akira Hamada, Kenichi Suda, Toshio Fujino Shuta Ohara, Junichi Soh, Tetsuya Mitsudomi
  • Organizer: 第79回日本癌学会総会