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Development of novel therapy and diagnosis targeted for signal transduction regarding drug tolerance in lung cancer

Research Project

Project/Area Number 19K08608
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53030:Respiratory medicine-related
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

YAMADA TADAAKI  京都府立医科大学, 医学(系)研究科(研究院), 准教授 (00507048)

Co-Investigator(Kenkyū-buntansha) 高山 浩一  京都府立医科大学, 医学(系)研究科(研究院), 教授 (50274444)
内野 順治  京都府立医科大学, 医学(系)研究科(研究院), 准教授 (80432946)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywords治療抵抗性 / 分子標的治療 / 薬剤耐性 / 肺癌 / がん分子標的治療 / EGFR / ALK / 癌分子標的治療
Outline of Research at the Start

本研究は、EGFRおよびALK遺伝子異常を有する肺がんにおける「分子標的治療の初期抵抗に
関わるシグナル指向性」を明らかにする。
具体的には、治療導入時に誘導される薬剤抵抗性細胞の分子機構の解明とその克服治療法の開発ならびに治療開始前に存在する治療抵抗性因子の同定を目指す。本課題に相当するin vitroおよびin vivo研究を通じた「分子標的治療の初期抵抗性」を解明した後、臨床検体を用いて効果予測に関わる候補因子の臨床的重要性について評価を行う。以上の研究成果を基盤に「初期抵抗性」細胞の出現阻止を目指した新規治療法およびバイオマーカーの開発を通じて、臨床応用に発展させることを目的にする。

Outline of Final Research Achievements

1) According to lung cancer with EGFR mutations, activated AXL was associated with maintaining cell survival and inducing the emergence of cells tolerant to EGFR inhibitor. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to EGFR inhibitors and the emergence of osimertinib-tolerant cells.
2) According to lung cancer with ALK fusion genes, NRG1-HER3 activation, mediated through ZEB1 proteins, help maintain cell survival and induce the emergence of ALK-TKI-tolerant cells. Thus, HER3 activation plays a pivotal role in the emergence ofALK-TKI-tolerant cells and the inhibition of HER3 signals combined with ALK-TKIs dramatically improves treatment outcomes for ALK-rearranged lung cancer.

Academic Significance and Societal Importance of the Research Achievements

難治性腫瘍である肺がんにおいて薬剤耐性は治療の最大の障壁である。近年、肺がんに対する分子標的薬が臨床応用された。しかしながら、肺がんの一部は治療抵抗を示し、早期に薬剤耐性を生じることが課題である。近年、治療抵抗性細胞の存在が、薬剤感受性の低下を促し、最終的に耐性機構を獲得することが報告され、注目されている。本研究ではEGFR遺伝子変異やALK融合遺伝子変異を有する肺がんを研究対象に複数の治療抵抗性機構を明らかにするとともに新規併用治療を提唱した。特に、本研究成果を基に、EGFR変異肺がんのAXLシグナル阻害を検証する第1相の治験が本邦にて実施され、臨床への還元が実現している。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (19 results)

All 2022 2021 2020 2019 2018 Other

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 3 results) Presentation (10 results) (of which Int'l Joint Research: 3 results,  Invited: 4 results) Book (2 results) Remarks (2 results)

  • [Journal Article] HER3 activation contributes toward the emergence of ALK inhibitor-tolerant cells in ALK-rearranged lung cancer with mesenchymal features.2022

    • Author(s)
      Tanimura K, Yamada T, Okada K, Nakai K, Horinaka M, Katayama Y, Morimoto K, Ogura Y, Takeda T, Shiotsu S, Ichikawa K, Watanabe S, Morimoto Y, Iwasaku M, Kaneko Y, Uchino J, Taniguchi H, Yoneda K, Matoba S, Sakai T, Uehara H, Yano S, Kusaba T, Katayama R, Takayama K.
    • Journal Title

      NPJ Precis Oncol.

      Volume: 6 Issue: 1 Pages: 5-5

    • DOI

      10.1038/s41698-021-00250-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of c-Jun N-terminal kinase signaling increased apoptosis and prevented the emergence of ALK-TKI-tolerant cells in ALK-rearranged non-small cell lung cancer.2021

    • Author(s)
      Tanimura K, Yamada T, Horinaka M, Katayama Y, Fukui S, Morimoto K, Nakano T, Tokuda S, Morimoto Y, Iwasaku M, Kaneko Y, Uchino J, Yoneda K, Yano S, Sakai T, Takayama K.
    • Journal Title

      Cancer Lett.

      Volume: 522 Pages: 119-128

    • DOI

      10.1016/j.canlet.2021.09.018

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impact of tumor programmed death ligand-1 expression on osimertinib efficacy in untreated EGFR-mutated advanced non-small cell lung cancer: a prospective observational study.2021

    • Author(s)
      Yoshimura A, Yamada T, Okuma Y, Fukuda A, Watanabe S, Nishioka N, Takeda T, Chihara Y, Takemoto S, Harada T, Hiranuma O, Shirai Y, Nishiyama A, Yano S, Goto Y, Shiotsu S, Kunimasa K, Morimoto Y, Iwasaku M, Kaneko Y, Uchino J, Kenmotsu H, Takahashi T, Takayama K.
    • Journal Title

      Transl Lung Cancer Res.

      Volume: 10 Issue: 8 Pages: 3582-3593

    • DOI

      10.21037/tlcr-21-461

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ONO-7475, a Novel AXL Inhibitor, Suppresses the Adaptive Resistance to Initial EGFR-TKI Treatment in EGFR-Mutated Non?Small Cell Lung Cancer2020

    • Author(s)
      Okura N, Nishioka N, Yamada T, Taniguchi H, Tanimura K, Katayama Y, Yoshimura A, Watanabe S, Kikuchi T, Shiotsu S, Kitazaki T, Nishiyama A, Iwasaku M, Kaneko Y, Uchino J, Uehara H, Horinaka M, Sakai T, Tanaka K, Kozaki R, Yano S, Takayama K.
    • Journal Title

      Clinical Cancer Research

      Volume: 26 Issue: 9 Pages: 2244-2256

    • DOI

      10.1158/1078-0432.ccr-19-2321

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Taniguchi H, Yamada T, Wang R, Tanimura K, Adachi Y, Nishiyama A, Tanimoto A, Takeuchi S, Araujo LH, Boroni M, Yoshimura A, Shiotsu S, Matsumoto I, Watanabe S, Kikuchi T, Miura S, Tanaka H, Kitazaki T, Yamaguchi H, Mukae H, Uchino J, Uehara H, Takayama K, Yano S.2018

    • Author(s)
      Taniguchi H, Yamada T, Wang R, Tanimura K, Adachi Y, Nishiyama A, Tanimoto A, Takeuchi S, Araujo LH, Boroni M, Yoshimura A, Shiotsu S, Matsumoto I, Watanabe S, Kikuchi T, Miura S, Tanaka H, Kitazaki T, Yamaguchi H, Mukae H, Uchino J, Uehara H, Takayama K, Yano S.
    • Journal Title

      Nat Commun.

      Volume: 10 Issue: 1 Pages: 259-259

    • DOI

      10.1038/s41467-018-08074-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Impact of PD-L1 expression on osimertinib efficacy in untreated EGFR-mutated NSCLC: a prospective observational study2022

    • Author(s)
      西岡直哉, 山田忠明, 吉村彰紘, 大熊裕介, 福田滉仁, 渡部聡, 竹田隆之, 千原佑介, 竹本真之輔, 原田大司, 平沼修, 白井由紀奈, 西山明宏, 矢野聖二, 後藤康洋, 塩津伸介, 國政啓, 釼持広知, 高橋利明, 高山浩一
    • Organizer
      第19回日本臨床腫瘍学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 肺がん分子標的治療の耐性克服2022

    • Author(s)
      山田忠明、髙山浩一
    • Organizer
      第62回日本呼吸器学会総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] EGFR遺伝子変異陽性肺がんにおけるEGFR-TKI耐性後の治療戦略2021

    • Author(s)
      山田忠明、髙山浩一
    • Organizer
      第62回日本肺癌学会総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Activation of HER3 signal yields tolerant cells to ALK inhibitors in ALK-rearranged lung cancer2021

    • Author(s)
      Keiko Tanimura, Tadaaki Yamada, Kohtaroh Okada, Kazue Yoneda, Junji Uchino, Ryohei Katayama, Koichi Takayama
    • Organizer
      第25回アジア太平洋呼吸器学会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ONO-7475, a novel AXL inhibitor, suppresses the emergence and maintenance of tolerant cells to initial EGFR-TKI treatment in EGFR-mutated non-small lung cancer2021

    • Author(s)
      Tadaaki Yamada, Naoko Okura, Naoya Nishioka, Hirokazu Taniguchi, Kohei Tanaka, Ryohei Kozaki, Seiji Yano, Koichi Takayama
    • Organizer
      第25回アジア太平洋呼吸器学会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ドライバー遺伝子変異肺癌の治療抵抗性克服を目指した新規治療法の開発2021

    • Author(s)
      山田忠明、髙山浩一
    • Organizer
      第80回日本癌学会総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] EGFR遺伝子変異陽性非小細胞肺がんのオシメルチニブ初回治療における腫瘍内AXL発現の意義を検討する多施設共同前向き観察研究2021

    • Author(s)
      吉村彰紘、山田忠明、谷村恵子、大熊裕介、福田滉仁、渡部聡、西岡直哉、竹田隆之、千原佑介、竹本真之輔、原田大司、平沼修、白井由紀奈、西山明宏、矢野聖二、後藤康洋、塩津伸介、國政啓、釼持広知、高橋利明、髙山浩一
    • Organizer
      第62回日本肺癌学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Novel therapeutic strategies for drug tolerance in NSCLC with driver oncogenes2021

    • Author(s)
      Tadaaki Yamada, Seiji Yano
    • Organizer
      第18回日本臨床腫瘍学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Driver遺伝子変異肺がんにおける初期治療抵抗性機構の解明2020

    • Author(s)
      山田忠明
    • Organizer
      第61回日本肺癌学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] AXL confers intrinsic resistance to osimertinib and the emergence of tolerant cells2019

    • Author(s)
      Hirokazu Taniguchi, Tadaaki Yamada, Rong Wang, Keiko Tanimura, Akihiro Nishiyama, Azusa Tanimoto, Yuta Adachi, Shinji Takeuchi, Hiroyuki Yamaguchi, Minoru Fukuda, Koichi Takayama, Hiroshi Mukae, Seiji Yano
    • Organizer
      第110回アメリカ癌学会
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Book] EGFR阻害薬についての研究の動向2021

    • Author(s)
      山田忠明
    • Total Pages
      7
    • Publisher
      科学評論社
    • Related Report
      2021 Annual Research Report
  • [Book] 肺がん分子標的治療の進歩2021

    • Author(s)
      山田忠明
    • Total Pages
      11
    • Publisher
      京都府立医科大学雑誌
    • Related Report
      2021 Annual Research Report
  • [Remarks] 肺がんの新たな治療抵抗性メカニズムを発見

    • URL

      https://www.kpu-m.ac.jp/doc/news/2022/files/29455.pdf

    • Related Report
      2021 Annual Research Report
  • [Remarks] JNK シグナル活性化に起因した ALK 阻害薬の初期抵抗性に関する論文掲載について

    • URL

      https://www.kpu-m.ac.jp/doc/news/2021/files/28379.pdf

    • Related Report
      2021 Annual Research Report

URL: 

Published: 2019-04-18   Modified: 2023-01-30  

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