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Development of therapy for overcoming resistance to mutant selective EGFR-TKI due to persistance of apoptosis

Research Project

Project/Area Number 17K09649
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionKanazawa University

Principal Investigator

TAKEUCHI SHINJI  金沢大学, 附属病院, 講師 (90565384)

Project Period (FY) 2017-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsEGFR変異 / 非小細胞肺癌 / アポトーシス / Osimertinib / HDAC阻害薬 / EGFR変異肺がん / BIM遺伝子多型 / HDAC3 / 癌 / トランスレーショナルリサーチ
Outline of Final Research Achievements

The BIM deletion polymorphism is associated with apoptosis resistance to EGFR-TKIs, such as gefitinib, in NSCLC harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against osimertinib, a mutant selective EGFR-TKI.
EGFR-mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to osimertinib and this resistance was overcome by combined use with vorinostat in vitro and in vivo. Experiments with homozygous BIM deletion-positive EGFR-mutated NSCLC cells revealed that vorinostat increased the expression of active BIM protein and induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating EGFR-mutated lung cancers carrying the BIM deletion polymorphism.

Academic Significance and Societal Importance of the Research Achievements

BIM遺伝子多型は少量の血液で解析が可能で、患者への侵襲が少なく、簡便かつ正確に解析することができるため、薬剤耐性のバイオマーカーとして非常に有望である。本研究により、EGFR変異肺癌の標準治療であるOsimertinibの耐性にもBIM遺伝子多型が影響しており、HDAC阻害薬であるVorinostat併用治療が有効であることが示唆された。今後、BIM遺伝子多型をバイオマーカーとしたHDAC阻害薬併用治療の臨床開発が進むことが期待される。

Report

(5 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (14 results)

All 2020 2019 2018 2017

All Journal Article (11 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 10 results,  Open Access: 8 results) Presentation (3 results) (of which Invited: 1 results)

  • [Journal Article] Phase I study of vorinostat with gefitinib in BIM deletion polymorphism/epidermal growth factor receptor mutation double-positive lung cancer.2020

    • Author(s)
      Shinji Takeuchi, Tetsunari Hase, et al.
    • Journal Title

      Cancer science

      Volume: 111 Issue: 2 Pages: 561-570

    • DOI

      10.1111/cas.14260

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Resminostat, a histone deacetylase inhibitor, circumvents tolerance to EGFR inhibitors in EGFR-mutated lung cancer cells with <i>BIM</i> deletion polymorphism2020

    • Author(s)
      Arai S, Yano S, et al.
    • Journal Title

      The Journal of Medical Investigation

      Volume: 67 Issue: 3.4 Pages: 343-350

    • DOI

      10.2152/jmi.67.343

    • NAID

      130007936892

    • ISSN
      1343-1420, 1349-6867
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of ALK-Rearranged Lung Cancer.2020

    • Author(s)
      Sachiko Arai, Shinji Takeuchi, Koji Fukuda, Hirokazu Taniguchi, Akihiro Nishiyama, Azusa Tanimoto, Miyako Satouchi, Kaname Yamashita, Koshiro Ohtsubo, Shigeki Nanjo, Toru Kumagai, Ryohei Katayama, Makoto Nishio, Mei-Mei Zheng, Yi-Long Wu, Hiroshi Nishihara, Takushi Yamamoto, Mitsutoshi Nakada, Seiji Yano
    • Journal Title

      Journal of thoracic oncology

      Volume: 15 Issue: 5 Pages: 752-765

    • DOI

      10.1016/j.jtho.2020.01.001

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Epithelial-to-Mesenchymal Transition Is a Mechanism of ALK Inhibitor Resistance in Lung Cancer Independent of ALK Mutation Status.2019

    • Author(s)
      Fukuda K, Takeuchi S,Yano S, et al.
    • Journal Title

      Cancer Res

      Volume: 79(7) Issue: 7 Pages: 1658-1670

    • DOI

      10.1158/0008-5472.can-18-2052

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Notch3-dependent β-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC.2018

    • Author(s)
      Arasada RR, Shilo K, Yamada T, Zhang J, Yano S, Ghanem R, Wang W, Takeuchi S, Fukuda K, Katakami N, Tomii K, Ogushi F, Nishioka Y, Talabere T, Misra S, Duan W, Fadda P, Rahman MA, Nana-Sinkam P, Evans J, Amann J, Tchekneva EE, Dikov MM, Carbone DP.
    • Journal Title

      Nat Commun.

      Volume: 9 Issue: 1 Pages: 3198-3198

    • DOI

      10.1038/s41467-018-05626-2

    • NAID

      120006949473

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation.2017

    • Author(s)
      Takeuchi S, Fukuda K, Yamada T, Arai S, Takagi S, Ishii G, Ochiai A, Iwakiri S, Itoi K, Uehara H, Nishihara H, Fujita N, Yano S.
    • Journal Title

      Cancer Sci.

      Volume: 108 Issue: 4 Pages: 696-703

    • DOI

      10.1111/cas.13190

    • NAID

      120006306235

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer.2017

    • Author(s)
      Tanimoto A, Takeuchi S, Arai S, Fukuda K, Yamada T, Roca X, Ong ST, Yano S.
    • Journal Title

      Clin Cancer Res.

      Volume: 23 Issue: 12 Pages: 3139-3149

    • DOI

      10.1158/1078-0432.ccr-16-2271

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Impact of MET inhibition on small-cell lung cancer cells showing aberrant activation of the hepatocyte growth factor/MET pathway.2017

    • Author(s)
      Taniguchi H, Yamada T, Takeuchi S, Arai S, Fukuda K, Sakamoto S, Kawada M, Yamaguchi H, Mukae H, Yano S.
    • Journal Title

      Cancer Sci.

      Volume: 108 Issue: 7 Pages: 1378-1385

    • DOI

      10.1111/cas.13268

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phase I study of combined therapy with vorinostat and gefitinib to treat <i>BIM</i> deletion polymorphism-associated resistance in <i>EGFR</i>-mutant lung cancer (VICTROY-J): a study protocol2017

    • Author(s)
      Takeuchi S, Yoshimura K, Fujiwara T, Ando M, Shimizu S, Nagase K, Hasegawa Y, Takahashi T, Katakami N, Inoue A, Yano S.
    • Journal Title

      The Journal of Medical Investigation

      Volume: 64 Issue: 3.4 Pages: 321-325

    • DOI

      10.2152/jmi.64.321

    • NAID

      130006105349

    • ISSN
      1343-1420, 1349-6867
    • Related Report
      2017 Research-status Report
  • [Journal Article] In vivo imaging xenograft models for the evaluation of anti-brain tumor efficacy of targeted drugs.2017

    • Author(s)
      Kita K, Arai S, Nishiyama A, Taniguchi H, Fukuda K, Wang R, Yamada T, Takeuchi S, Tange S, Tajima A, Nakada M, Yasumoto K, Motoo Y, Murakami T, Yano S.
    • Journal Title

      Cancer Med

      Volume: 6 Issue: 12 Pages: 2972-2983

    • DOI

      10.1002/cam4.1255

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 肺癌のアポトーシス抵抗性に起因する 分子標的薬耐性を克服する橋渡し研究2018

    • Author(s)
      竹内 伸司
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 医師主導治験による肺がんの新規分子標的治療の開発2017

    • Author(s)
      竹内伸司
    • Organizer
      第15回日本臨床腫瘍学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] New therapeutic strategies for overcoming resistance to targeted drugs in lung cancer by HDAC inhibition2017

    • Author(s)
      竹内伸司
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
    • Invited

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Published: 2017-04-28   Modified: 2022-01-27  

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