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Functional analysis of coexisting RBM10 mutations in EGFR-mutated lung cancer

Research Project

Project/Area Number 21K15546
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 50020:Tumor diagnostics and therapeutics-related
Research InstitutionKanazawa University

Principal Investigator

Nanjo Shigeki  金沢大学, 附属病院, 講師 (00722555)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Keywords分子標的薬耐性 / RBM10遺伝子変異 / EGFR変異肺癌 / スプライシング因子 / アポトーシス / Bcl-x / EGFR変異肺がん / RBM10 / 薬剤耐性
Outline of Research at the Start

肺がん分子標的治療は、EGFRなど薬物療法の標的となるoncoproteinを有する患者に対す
るEGFR阻害薬の開発などによって改善してきたが、根治や長期生存は未だに限定的であり、この根底には、腫瘍の不均一性があると考えられる。がん遺伝子パネル検査が保険承認され、同時に様々な遺伝子に変異が起こることが明らかになり、EGFR変異肺がんの約8%において、mRNAスプライシング制御因子であるRBM10遺伝子にも変異が起こっており、本研究では、分子標的治療へのスプライシング制御因子を介した薬剤耐性機構を解明し、耐性を克服する新規治療法の開発を目的とする。

Outline of Final Research Achievements

In EGFR lung cancer patients, RBM10 mutation as a co-mutation occurred in 7.6% of patients in addition to oncogene EGFR mutation, and knockout of RBM10 attenuated apoptosis induced by EGFR inhibitors. We also found that PFS and response rate to EGFR inhibitors were significantly lower in patients with coexisting RBM10 mutations. In addition, the ratio of apoptosis-promoting factor Bcl-xS to apoptosis-resisting factor Bcl-xL was decreased by RBM10 deficiency. Then, we showed that the combination of a Bcl-xL inhibitor with an EGFR inhibitor can overcome this intrinsic resistance.

Academic Significance and Societal Importance of the Research Achievements

第3世代のEGFRチロシンキナーゼ阻害薬 (EGFR-TKI) であるOsimertinibは、EGFR遺伝子変異陽性肺癌 (EGFR肺癌)に対してよく奏効し、高い有効性を示す。しかしながら、当初から腫瘍が縮小しない、初期耐性も2-3割に認め、この原因解明と耐性克服が重要な課題であるが、申請者は本研究においてその機序と克服法を示した。
本研究において、肺癌の分子標的薬耐性の新たなメカニズムが同定されるとともに、治療法の候補が見つかったことから、近い将来耐性克服を目指す臨床試験が行われ、成果が患者に還元される可能性が生まれた。

Report

(3 results)
  • 2023 Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (12 results)

All 2023 2022 2021

All Journal Article (3 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (8 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Book (1 results)

  • [Journal Article] Methylation of Tumor Suppressive miRNAs in Plasma from Patients With Pancreaticobiliary Diseases2022

    • Author(s)
      OHTSUBO KOUSHIRO、MIYAKE KUNIO、ARAI SACHIKO、FUKUDA KOJI、SUZUKI CHIAKI、KOTANI HIROSHI、TANIMOTO AZUSA、NISHIYAMA AKIHIRO、NANJO SHIGEKI、YAMASHITA KANAME、TAKEUCHI SHINJI、YANO SEIJI
    • Journal Title

      Cancer Diagnosis Prognosis

      Volume: 2 Issue: 3 Pages: 378-383

    • DOI

      10.21873/cdp.10120

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer2022

    • Author(s)
      Nanjo S, Wu W, Karachaliou N, Blakely C, Suzuki J, Chou Y, Ali S, Kerr L, Olivas V, Shue J, Rotow J, Mayekar M, Haderk F, Chatterjee N, Urisman A, Yeo J, Skanderup A, Tan A, Tam W, Arrieta O, Hosomichi K, Nishiyama A, Yano S, Kirichok Y, Tan D, Rosell R, Okimoto R, Bivona T.
    • Journal Title

      Journal of Clinical Investigation

      Volume: 132 Issue: 13

    • DOI

      10.1172/jci145099

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A novel approach for the non-invasive diagnosis of pulmonary nodules using low-depth whole-genome sequencing of cell-free DNA2022

    • Author(s)
      Zhang Bin、Liang Han、Liu Weiran、Zhou Xinlan、Qiao Sitan、Li Fuqiang、Tian Pengfei、Li Chenguang、Ma Yuchen、Zhang Hua、Zhang Zhenfa、Nanjo Shigeki、Russo Alessandro、Puig-Butille? Joan Anton、Wu Kui、Wang Changli、Zhao Xin、Yue Dongsheng
    • Journal Title

      Translational Lung Cancer Research

      Volume: 11 Issue: 10 Pages: 2094-2110

    • DOI

      10.21037/tlcr-22-647

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 脳脊髄液腫瘍由来DNA(CSF-tDNA)を用いたEGFR変異肺がん中枢神経系転移における治療最適化2023

    • Author(s)
      南條成輝
    • Organizer
      第20回日本臨床腫瘍学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] EGFR変異肺癌において併存するRBM10遺伝子変異によるEGFR-TKI耐性~なぜEGFR L858R変異に効きにくいのか~2022

    • Author(s)
      南條成輝
    • Organizer
      第62回日本呼吸器学会学術講演会
    • Related Report
      2022 Research-status Report
  • [Presentation] EGFR 変異肺癌におけるRBM10遺伝子変異共存を通してみえてきた遺伝的な不均一性の克服 ~共存遺伝子による層別化と個別化治療~2022

    • Author(s)
      南條成輝
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] Co-mutation in splicing factor with EGFR mutations limits sensitivity to EGFR-TKIs ~Why are EGFR-TKIs less effective against EGFR L858R?~2022

    • Author(s)
      南條成輝
    • Organizer
      第63回日本肺癌学会学術集会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR mutant lung cancer2022

    • Author(s)
      Shigeki Nanjo
    • Organizer
      第19回日本臨床腫瘍学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 転移性EGFR変異肺がんにおいて併存するRBM10遺伝子変異によるEGFR-TKI阻害薬耐性2021

    • Author(s)
      南條成輝
    • Organizer
      第30回日本がん転移学会学術集会・総会
    • Related Report
      2021 Research-status Report
  • [Presentation] Co-mutation in splicing factor with EGFR mutations limits sensitivity to EGFR-TKIs ~Why are EGFR-TKIs less effective against EGFR L858R?~2021

    • Author(s)
      Shigeki Nanjo
    • Organizer
      The 25th Congress of the Asian Pacific Society of Respirology
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR mutant lung cancer2021

    • Author(s)
      Shigeki Nanjo
    • Organizer
      第62回日本肺癌学会学術集会
    • Related Report
      2021 Research-status Report
  • [Book] 最新臨床肺癌学 日本臨牀 80巻増刊号8(通巻第1225号)2022

    • Author(s)
      南條成輝、矢野聖二
    • Total Pages
      6
    • Publisher
      日本臨牀
    • Related Report
      2022 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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