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Cytoskeleton-YAP axis regulates lung cancer resistanc: From mechanism to therapy

Research Project

Project/Area Number 20K08580
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 InstitutionMiyagi Prefectural Hospital Organization Miyagi Cancer Center

Principal Investigator

Fukuhara Tatsuro  地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), がん先進治療開発研究部, 特任研究員 (80400365)

Co-Investigator(Kenkyū-buntansha) 田中 伸幸  地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), がん先進治療開発研究部, 部長 (60280872)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsがん / 細胞骨格 / 癌
Outline of Research at the Start

EGFRチロシンキナーゼ阻害剤は非小細胞肺癌(NSCLC)に対する優れた治療薬であるが、耐性が課題である。多くの癌で高頻度に認められる細胞骨格系の活性化は、Hippo経路のエフェクターであるYAPを活性化することが明らかとなった。そこで、本研究では耐性獲得における新たなパラダイムとして「細胞骨格-YAP系」を提唱し、両者の連携による耐性獲得機構を解明する。肺癌モデルマウスを用いることで、独創的なin vivo治療モデルを樹立し、このパスウェイを標的とした治療モデルを構築し、治療抵抗性肺癌を制御する基礎研究を確立する。

Outline of Final Research Achievements

The receptors for growth factors play a role in controlling the physical environment of cancer by transmitting mechanical signals, such as changes in cell shape and movement, in addition to signals that promote cell growth. Based on the analysis of YAP in cells with mutated EGFR, YAP is activated by EGFR. Studying YAP target genes also showed that EGFR signals activate the transcription of these genes. On the other hand, when the cytoskeleton is inhibited, it causes an increase in cell stress and, at the same time, inhibits cell movement, invasion, and growth. These findings suggest that YAP collaborates with the actin cytoskeleton to enhance the harmful characteristics of lung cancer.

Academic Significance and Societal Importance of the Research Achievements

本研究では肺がんと細胞骨格の関連に関する示唆に富む結果を得た。肺がんは治療抵抗性が問題となっており、本研究により明らかとなった細胞骨格によるアポトーシス抵抗性の発揮は、新たな治療戦略の設定に寄与する可能性がある。肺がんの新たな治療法開発に繋がれば社会的貢献となることが期待される。

Report

(3 results)
  • 2023 Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (17 results)

All 2022 2021 2020

All Journal Article (11 results) (of which Peer Reviewed: 11 results,  Open Access: 8 results) Presentation (6 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results)

  • [Journal Article] Phase II study of carboplatin-paclitaxel alone or with bevacizumab in advanced sarcomatoid carcinoma of the lung: HOT1201/NEJ0242022

    • Author(s)
      Oizumi Satoshi、Takamura Kei、Harada Toshiyuki、Tachihara Motoko、Morikawa Naoto、Honda Ryoichi、Watanabe Satoshi、Asao Tetsuhiko、Kunisaki Mamoru、Fukuhara Tatsuroら, Hokkaido Lung Cancer Clinical Study Group
    • Journal Title

      International Journal of Clinical Oncology

      Volume: 27 Issue: 4 Pages: 676-683

    • DOI

      10.1007/s10147-021-02113-5

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] First-line nivolumab+ ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients2022

    • Author(s)
      O’Byrne K.J.、Lee K.H.、Kim S.-W.、Park K.、Nishio M.、Sakai H.、Ohe Y.、Fukuhara T.、Kang J.-H.、Daga H.、Yu C.-J.、Hotta K.、Tanaka H.、Takeda M.、Yokoyama T.、Nathan F.E.、Lee J.-S.
    • Journal Title

      ESMO Open

      Volume: 7 Issue: 1 Pages: 100394-100394

    • DOI

      10.1016/j.esmoop.2022.100394

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] MK‐6, a novel not‐α IL‐2, elicits a potent antitumor activity by improving the effector to regulatory T cell balance2021

    • Author(s)
      Kobayashi Maki、Kojima Katsuhiko、Murayama Kazutaka、Amano Yuji、Koyama Takashi、Ogama Naoko、Takeshita Toshikazu、Fukuhara Tatsuro、Tanaka Nobuyuki
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 11 Pages: 4478-4489

    • DOI

      10.1111/cas.15127

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] GPI-80 Augments NF-κB Activation in Tumor Cells2021

    • Author(s)
      Takeda Yuji、Kurota Yuta、Kato Tomoyuki、Ito Hiromi、Araki Akemi、Nara Hidetoshi、Saitoh Shinichi、Tanaka Nobuyuki、Tsuchiya Norihiko、Asao Hironobu
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 21 Pages: 12027-12027

    • DOI

      10.3390/ijms222112027

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Randomized phase 2 study comparing irinotecan versus amrubicin as maintenance therapy after first‐line induction therapy for extensive disease small cell lung cancer.2021

    • Author(s)
      Tanaka Hisashi、Hasegawa Yukihiro、Fujita Yuka、Nakamura Atsushi、Kikuchi Eiki、Kawai Yasutaka、Harada Toshiyuki、Watanabe Naomi、Yokouchi Hiroshi、Usui Kazuhiro、Saito Ryota、Watanabe Hiroshi、Masuda Tomomi、Fukuhara Tatsuro、Kudo Keita、Honda Ryoichi、Oizimi Satoshi、Maemondo Makoto、Inoue Akira、Morikawa Naoto
    • Journal Title

      Thoracic Cancer

      Volume: 12 Issue: 14 Pages: 2113-2121

    • DOI

      10.1111/1759-7714.14048

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] First‐line pembrolizumab vs chemotherapy in metastatic non‐small‐cell lung cancer: KEYNOTE‐024 Japan subset2021

    • Author(s)
      Satouchi Miyako、Nosaki Kaname、Takahashi Toshiaki、Nakagawa Kazuhiko、Aoe Keisuke、Kurata Takayasu、Sekine Akimasa、Horiike Atsushi、Fukuhara Tatsurora
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 12 Pages: 5000-5010

    • DOI

      10.1111/cas.15144

    • NAID

      120007170522

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The CLIP1-LTK fusion is an oncogenic driver?in non‐small‐cell lung cancer2021

    • Author(s)
      Izumi Hiroki、Matsumoto Shingo、Liu Jie、Tanaka Kosuke、Mori Shunta、Hayashi Kumiko、Kumagai Shogo、Shibata Yuji、Hayashida Takuma、Watanabe Kana、Fukuhara Tatsuroら
    • Journal Title

      Nature

      Volume: 600 Issue: 7888 Pages: 319-323

    • DOI

      10.1038/s41586-021-04135-5

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Treatment with immune checkpoint inhibitors after EGFR-TKIs in EGFR-mutated lung cancer.2021

    • Author(s)
      Ito Takashi、Nagashima Hiromi、Akiyama Masachika、Utsumi Yu、Sato Hideomi、Chiba Shinji、Sugai Mayu、Ube Kenji、Mori Yoshiaki、Watanabe Kana、Fukuhara Tatsuro、Maemondo Makoto
    • Journal Title

      Thoracic Cancer

      Volume: 13 Issue: 3 Pages: 386-393

    • DOI

      10.1111/1759-7714.14267

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evaluation of plasma EGFR mutation as an early predictor of response of erlotinib plus bevacizumab treatment in the NEJ026 study.2020

    • Author(s)
      T.Fukuhara, H.Saito, N.Furuya, K.Watanabe, S.Sugawara, S.Iwasawa, Y.Tsunezuka, O.Yamaguchi, M.Okada, K.Yoshimori, I.Nakachi, A.Genma, K.Azuma, F.Kurimoto, Y.Tsubata, Y.Fijita, H.Nagashima, G.Asai, S.Watanabe, M.Miyazaki, K.Hagiwara, T.Nukiwa, S.Morita, K.Kobayashi, M.Maemondo
    • Journal Title

      EBioMedicine

      Volume: 57 Pages: 102861-102861

    • DOI

      10.1016/j.ebiom.2020.102861

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] First-line pemburilizumzb vs chemotherarapy in metastatic non-small-cerll lung cancer: KEYNOTE-024 japan subset.2020

    • Author(s)
      M.Satouchi, K.Nosaki, T.Takahashi, K.Nakagawa, K.Aoe, T.Kurata, A.Sekine, A.Horiike, T.Fukuhara, S.Sugawara, S.Umemura, H.Saka, I.Okamoto, N.Yamamoto, H.Sakai, K.Kishi, N.Katakami, H.Horinouti, T.Hida, H.Okamoto, S.Atagi, T.Ohira, S.Rong Han, K.Noguchi, V,Ebiana, K.Hotta
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 12 Pages: 4480-4489

    • DOI

      10.1111/cas.14647

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Randomized phase II trial of uracil/tegafur and cisplatin versus pemetrexed and cisplatin with concurrent thoracis radiotherapy for locally advanced unresectable stage III non-squamous non-small cell lung cancer: NJLCG10012020

    • Author(s)
      K.Watanabe, Y.Toi, A.Nakamura, R.Chiba, M.Akiyama, J.Sakakibara-Konishi, H.Tanaka, N.Yoshimura, E.Miyauchi, T.Nakagawa, R.Igusa, H.Minemura, Y.Mori, K.Fujimoto, H.Matsushita, F.Takahashi, T.Fukuhara, A.Inoue, S.Sugawara, M.Maemonndo
    • Journal Title

      Transl Lung Cancer Res.

      Volume: 10 Issue: 2 Pages: 712-722

    • DOI

      10.21037/tlcr-20-721

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] A novel not-α IL-2 elicits potent anti-tumor activity in mice by improving the effector to regulatory T cell balance.2021

    • Author(s)
      小林真紀、小鎌直子、小嶋克彦、福原達朗、田中伸幸
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] A Prospective Observational Study of Osimertinib Using Plasma Concentrations in NSCLC With Acquired EGFR T790M Mutation.2021

    • Author(s)
      T. Nakagawa, T. Fukuhara, K. Imai, R. Igusa, H. Yokota, K. Watanabe, A. Suzuki, M. Morita, A. Inoue, M. Miura, Y. Minamiya, M. Maemondo
    • Organizer
      2021 World Conference on Lung Cancer
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Overall survival and ctDNA analysis of bevacizumab plus erlotinib treatment for EGFR-mutant NSCLC patients in NEJ0262021

    • Author(s)
      福原達朗, 古谷直樹, 齋藤春洋, 渡邉香奈, 菅原俊一, 岩沢俊一郎, 常塚宣男, 山口央, 岡田守人, 吉森浩三, 仲地一郎, 弦間昭彦, 東公一, 萩原弘一, 貫輪敏博, 森田智視, 小林国彦, 前門戸任
    • Organizer
      第18回日本臨床腫瘍学会学術集会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Final overall survival analysis of bevacizumab plus erlotinib treatment for NSCLC patients harboring activating EGFR-mutations (NEJ026)2020

    • Author(s)
      M Maemondo, T Fukuhara, H Saito, N Furuya, K Watanabe, S Sugawara, S Iwasawa, Y Tsunezuka, O Yamaguchi, M Okada, K Yoshimori, I Nakachi, A Genma, K Azuma, K Hagiwara, T Nukiwa, S Morita, K Kobayashi
    • Organizer
      ASCO Annual Meeting Virtual
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] First-line pemburilizumzb vs chemotherarapy in metastatic non-small-cerll lung cancer: KEYNOTE-024 japan subse2020

    • Author(s)
      KJ O'Byrne, KH Lee, S-W Kim, K Park, M Nishio, H Sakai, Y Ohe, T Fukuhara, J Kang, H Daga, M Takeda, T Yakoyama, FE Nathan, JLee
    • Organizer
      ESMO Virtual
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] EGFR阻害薬で治療された腫瘍におけるT790M耐性変異および活性型変異のシスおよびトランス頻度2020

    • Author(s)
      平野邦夫, 渡邉香奈, 秋山真親, 千葉亮祐, 長島広相, 佐藤英臣, 菅井万優, 寺崎浩司, 福原達朗, 前門戸
    • Organizer
      第61回日本肺癌学会学術集会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2025-01-30  

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