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Elucidation of the mechanism of resistance to apoptosis in ALK rearranged NSCLC

Research Project

Project/Area Number 18K15922
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53030:Respiratory medicine-related
Research InstitutionKanazawa University

Principal Investigator

Tanimoto Azusa  金沢大学, がん進展制御研究所, 助教 (90776444)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
KeywordsALK / Mcl-1 / Noxa / Proteasome / p53 / アポトーシス / ALK融合遺伝子陽性肺癌 / 自然耐性 / ALK阻害薬 / 肺癌 / ALK融合遺伝子 / 分子標的薬 / PUMA
Outline of Final Research Achievements

We used integrated clinical and next-generation sequencing data. ALK-rearranged NSCLC cell lines expressing wild-type or mutant TP53 were used to evaluate cellular apoptosis induced by ALK-TKIs.In 90 ALK-rearranged NSCLC patients who were treated with a selective ALK-TKI, alectinib, TP53 co-mutated patients showed significantly worse progression-free survival (PFS) than TP53 wild-type patients [median PFS, 11.7 months vs.NR; p=0.0008; hazard ratio, 0.33]. ALK-rearranged NSCLC cell lines which lost p53 function were resistant to alectinib-induced apoptosis, but a proteasome inhibitior, ixazommib markedly induced apoptosis in the alectinib-treated cells by increasing the expression of a pro-apoptotic protein, Noxa which bound to an anti-apoptotic protein, Mcl-1. In subcutaneous tumor models, combination of ixazomib and alectinib prominently induced tumor regression and apoptosis even though the tumors were generated from ALK-rearranged NSCLC cells with non-functional p53.

Academic Significance and Societal Importance of the Research Achievements

ALK融合遺伝子陽性肺癌の約1/4にTP53変異が共存しており、本来有効であるALK阻害薬の効果を減弱させる要因となっていることが明らかにした。TP53変異はEGFR遺伝子などの他のドライバー遺伝子変異陽性肺癌にも共存しており、本研究は選択的Mcl-1阻害薬の開発の意義が高めた。

Report

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

    (5 results)

All 2020 2019

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (4 results) (of which Invited: 1 results)

  • [Journal Article] Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression2020

    • Author(s)
      Tanimoto Azusa、Matsumoto Shingo、Takeuchi Shinji、Arai Sachiko、Fukuda Koji、Nishiyama Akihiro、Yoh Kiyotaka、Ikeda Takaya、Furuya Naoki、Nishino Kazumi、Ohe Yuichiro、Goto Koichi、Yano Seiji
    • Journal Title

      Clinical Cancer Research

      Volume: 27 Issue: 5 Pages: 1410-1420

    • DOI

      10.1158/1078-0432.ccr-20-2853

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] ALK融合遺伝子陽性肺癌におけるp53の機能低下に起因するALK阻害薬耐性の新規克服治療の開発2020

    • Author(s)
      谷本 梓
    • Organizer
      第86回日本呼吸器学会北陸地方会
    • Related Report
      2020 Annual Research Report
  • [Presentation] ALK 融合遺伝子陽性肺癌においてp53 の機能低下がもたらすALK-TKI 自然耐性の克服2019

    • Author(s)
      谷本 梓
    • Organizer
      第60回日本肺癌学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Proteasome inhibitor overcomes ALK-TKI resistance by p53 inactivation through Noxaexpression in EML4-ALK NSCLC2019

    • Author(s)
      谷本 梓
    • Organizer
      第17回日本臨床腫瘍学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 分子標的薬の自然耐性に着目した基礎研究と臨床応用への試み2019

    • Author(s)
      谷本 梓
    • Organizer
      第13回日本緩和医療薬学会年会
    • Related Report
      2019 Research-status Report
    • Invited

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Published: 2018-04-23   Modified: 2022-01-27  

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