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Exploring receptor type tyrosine kinases regulating Hippo pathway for the treatment of patients with head and neck cancer

Research Project

Project/Area Number 20K18477
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 57020:Oral pathobiological science-related
Research InstitutionHiroshima University

Principal Investigator

Ando Toshinori  広島大学, 病院(歯), 助教 (40754552)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsYAP / Hippo経路 / AXL / EGFR / 口腔扁平上皮癌 / 頭頸部扁平上皮癌 / 肺腺癌 / EGFR阻害薬耐性 / 受容体型チロシンキナーゼ / チロシンキナーゼ型受容体 / Hippo pathway / 頭頸部癌 / チロシンキナーゼ
Outline of Research at the Start

頭頸部に発生する癌では、Hippo経路の下流であるYAP/TAZという癌遺伝子が異常に活性化しており、腫瘍細胞の増殖能を亢進している。しかし、頭頸部癌でYAP/TAZが異常に活性化している詳細な機構は明らかになっていない。本研究では、YAP/TAZの活性化を促す受容体型チロシンキナーゼを同定することで、頭頸部癌の新たな分子標的薬の可能性を示すことを目的として研究を行う。

Outline of Final Research Achievements

The objective of this study is to clarify the mechanism by which AXL regulates the Hippo pathway and confers resistance to EGFR inhbitors. Database analysis revealed that AXL is the RTK most relevant to the Hippo pathway. AXL inhibitor treatment increased YAP phosphorylation and reduced CTGF/CYR61 expression in HNSCC and LUAC cells highly expressing AXL. Co-immunoprecipitation assay demonstrated that EGFR and AXL form a heterodimer, and siRNA knockdown of AXL induced EGFR inactivation and reduced CTGF/CYR61 expression. LATS1/2 knockout by CRISPR/Cas9 system rescued the phenotype mentioned above. AXL heterodimerizes with EGFR and activates YAP through EGFR-MOB1 axis, thereby conferring resistance to EGFR inhibitors. This suggests that combination therapy with AXL inhibitors and EGFR inhibitors may be a novel cancer therapeutic approach targeting YAP.

Academic Significance and Societal Importance of the Research Achievements

頭頸部扁平上皮癌(HNSCC)で遺伝子増幅・過剰発現、あるいは肺腺癌(LUAC)で活性化変異しているEGFRが、がん遺伝子のYAPを活性化して増殖を促進することを以前見出していた。しかしEGFR阻害薬単剤では再発や耐性が問題となっており、別の遺伝子によるYAP再活性化が関与する可能性が示唆されていた。本研究の成果は、AXLによるYAP活性化およびEGFR阻害薬耐性を付与する機構を解明することで,EGFR阻害薬の耐性を解除するためにAXL阻害薬を併用する新たな治療法の可能性を見出した.将来的にHNSCCおよびLUACを示す患者の治療効果を改善し,生命予後の延長をもたらす点で臨床的にも重要である.

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (6 results)

All 2022 Other

All Int'l Joint Research (1 results) Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (3 results) Remarks (1 results)

  • [Int'l Joint Research] University of California, San Diego(米国)

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Integrating Genetic Alterations and the Hippo Pathway in Head and Neck Squamous Cell Carcinoma for Future Precision Medicine2022

    • Author(s)
      Ando Toshinori、Okamoto Kento、Shintani Tomoaki、Yanamoto Souichi、Miyauchi Mutsumi、Gutkind J. Silvio、Kajiya Mikihito
    • Journal Title

      Journal of Personalized Medicine

      Volume: 12 Issue: 10 Pages: 1544-1544

    • DOI

      10.3390/jpm12101544

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] AXLによる新たなHippo経路制御機構の解明2022

    • Author(s)
      安藤 俊範, 岡本 健人, 柳本 惣市, 宮内 睦美
    • Organizer
      3学会合同学術大会(第32回日本口腔内科学会・第33回 日本臨床口腔病理学会・第35回日本口腔診断学会)
    • Related Report
      2022 Annual Research Report
  • [Presentation] AXL activates YAP and confers resistance to EGFR inhibitors in oral squamous cell carcinoma2022

    • Author(s)
      Okamoto K, Ando T, Kajiya M, Yanamoto S, Miyauchi M
    • Organizer
      第55回広島大学歯学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 口腔扁平上皮癌におけるAXLのYAP活性化およびEGFR阻害薬耐性機構の解2022

    • Author(s)
      岡本健人, 安藤俊範, 虎谷茂昭, 柳本惣市, 宮内睦美
    • Organizer
      第76回NPO法人 日本口腔科学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Remarks] 広島大学 研究者総覧

    • URL

      https://seeds.office.hiroshima-u.ac.jp/profile/ja.9750ed34c310fb91520e17560c007669.html

    • Related Report
      2022 Annual Research Report

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Published: 2020-04-28   Modified: 2024-01-30  

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