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Formation of a non-clinical research base for treatment aimed to eradicate lung cancer by targeted drugs

Research Project

Project/Area Number 19H03665
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 53030:Respiratory medicine-related
Research InstitutionKanazawa University

Principal Investigator

Yano Seiji  金沢大学, がん進展制御研究所, 教授 (30294672)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000)
Fiscal Year 2021: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2020: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Keywords分子標的薬 / 抵抗性 / EGFR変異 / ALK融合遺伝子 / NTRK1融合遺伝子 / 耐性 / EML4-ALK / 抵抗性細胞 / AXL / インスリン様増殖因子受容体 / 肺がん / IGF-1R / 転写因子 / FOXA1
Outline of Research at the Start

EGFR変異肺がん細胞株やALK融合遺伝子、RET融合遺伝子、MET変異
などのドライバー遺伝子異常を有する肺がん細胞株を用い、それぞれに対応する新世代分子標的薬(オシメルチニブ、アレクチニブなど)を暴露した際に適応・順応する分子機構を解明する。さらに、適応・順応を阻害しうる薬剤をスクリーニングし、in vitroおよび免疫不全マウスを用いたCDXモデル(可能ならPDXモデルも)において、腫瘍の根治が可能か否かを明らかにする。一方、分子標的薬に適応・順応する分子機構は腫瘍内あるいは腫瘍間で異なる多様性の存在が予想され、根治が得られない場合にはMEK阻害薬等の追加併用効果も検討する。

Outline of Final Research Achievements

Cancer cells exposed to targeted drugs emerge tolerant cells that allow some to survive as resistant cells and later proliferate. In this study, we found that EGFR-mutated lung cancer cells with low AXL expression emerge tolerant cells to the EGFR inhibitor osimertinib by increasing the expression of the transcription factor FOXA1 to activate IGF-1R. We further found that TP53 mutation and STAT3 activation induce apoptosis resistance to ALK inhibitors and cause ALK inhibitor tolerance in ALK rearranged lung cancer cells. In addition, combined use of proteasome inhibitors or STAT3 inhibitors could augment the efficacy of ALK inhibitors against ALK rearranged lung cancer cells.

Academic Significance and Societal Importance of the Research Achievements

分子標的薬は標的を有するがん患者に著効するが、一部のがん細胞が抵抗性となって生き残り、再発する原因となる。本研究では一部のがん細胞が生き残るメカニズムとして正常細胞がもともと持っている蛋白質を活性化させたり、がん細胞が持っている遺伝子異常により細胞を死ににくくさせることを明らかにした。この研究成果が分子標的薬の治療効果を高める治療法開発に結び付くことが期待される。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (30 results)

All 2022 2021 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (13 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 13 results,  Open Access: 12 results) Presentation (14 results) (of which Int'l Joint Research: 5 results,  Invited: 4 results) Remarks (2 results)

  • [Int'l Joint Research] 南方医科大学(中国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis.2022

    • Author(s)
      Yanagimura N, Takeuchi S, Fukuda K, Arai S, Tanimoto A, Nishiyama A, Ogo N, Takahashi H, Asai A, Watanabe S, Kikuchi T, Yano S.
    • Journal Title

      NPJ Precis Oncol

      Volume: 6 Issue: 1 Pages: 11-11

    • DOI

      10.1038/s41698-022-00254-y

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Trametinib overcomes KRAS-G12V-induced osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR-mutant lung cancer2021

    • Author(s)
      Fukuda Koji、Otani Sakiko、Takeuchi Shinji、Arai Sachiko、Nanjo Shigeki、Tanimoto Azusa、Nishiyama Akihiro、Naoki Katsuhiko、Yano Seiji
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 9 Pages: 3784-3795

    • DOI

      10.1111/cas.15035

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [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
  • [Journal Article] Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer2020

    • Author(s)
      Wang Rong、Yamada Tadaaki、Kita Kenji、Taniguchi Hirokazu、Arai Sachiko、Fukuda Koji、Terashima Minoru、Ishimura Akihiko、Nishiyama Akihiro、Tanimoto Azusa、Takeuchi Shinji、Ohtsubo Koshiro、Wang Wei、Suzuki Takeshi、Yano Seiji et. al.
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 4607-4607

    • DOI

      10.1038/s41467-020-18442-4

    • NAID

      120007186801

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] MET amplification results in heterogeneous responses to osimertinib in EGFR ‐mutant lung cancer treated with erlotinib2020

    • Author(s)
      Nishiyama Akihiro、Takeuchi Shinji、Adachi Yuta、Otani Sakiko、Tanimoto Azusa、Sasaki Motoko、Matsumoto Shingo、Goto Koichi、Yano Seiji
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 10 Pages: 3813-3823

    • DOI

      10.1111/cas.14593

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [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] Glycogen synthase kinase‐3 inhibition overcomes epithelial‐mesenchymal transition‐associated resistance to osimertinib in EGFR ‐mutant lung cancer2020

    • Author(s)
      Fukuda Koji、Takeuchi Shinji、Arai Sachiko、Kita Kenji、Tanimoto Azusa、Nishiyama Akihiro、Yano Seiji
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 7 Pages: 2374-2384

    • DOI

      10.1111/cas.14454

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Caput Medusae-like Venous Dilatation in Lung Cancer2019

    • Author(s)
      Adachi Y, Yano S.
    • Journal Title

      Internal Medicine

      Volume: 58 Issue: 22 Pages: 3341-3342

    • DOI

      10.2169/internalmedicine.2577-18

    • NAID

      130007746035

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2019-11-15
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Patient‐derived xenograft models of non‐small cell lung cancer for evaluating targeted drug sensitivity and resistance2019

    • Author(s)
      Kenji Kita, Koji Fukuda, Hiro Takahashi, Azusa Tanimoto, Akihiro Nishiyama, Sachiko Arai, Shinji Takeuchi, Kaname Yamashita, Koshiro Ohtsubo, Sakiko Otani, Naohiro Yanagimura, Chiaki Suzuki, Hiroko Ikeda, Masaya Tamura, Isao Matsumoto, Seiji Yano
    • Journal Title

      Cancer Science

      Volume: 110(10) Issue: 10 Pages: 3215-3224

    • DOI

      10.1111/cas.14171

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Distribution and Activity of Lenvatinib in Brain Tumor Models of Human Anaplastic Thyroid Cancer Cells in Severe Combined Immune Deficient Mice2019

    • Author(s)
      Wang Rong、Yamada Tadaaki、Arai Sachiko、Fukuda Koji、Taniguchi Hirokazu、Tanimoto Azusa、Nishiyama Akihiro、Takeuchi Shinji、Yamashita Kaname、Ohtsubo Koshiro、Matsui Junji、Onoda Naoyoshi、Hirata Eishu、Taira Shu、Yano Seiji
    • Journal Title

      Molecular Cancer Therapeutics

      Volume: x Issue: 5 Pages: 947-56

    • DOI

      10.1158/1535-7163.mct-18-0695

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [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 Annual Research 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
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 分子標的薬抵抗性・耐性の治療標的.2021

    • Author(s)
      矢野聖二.
    • Organizer
      第62回日本肺癌学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 第二世代TRK阻害薬の耐性機構解明と耐性克服治療の探索.2021

    • Author(s)
      鈴木千晶, 矢野聖二,他.
    • Organizer
      第25回日本がん分子標的治療学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ALK 融合遺伝子陽性肺癌における STAT3 阻害薬の併用によるアポトーシス抵抗性の克服.2021

    • Author(s)
      柳村尚寛, 矢野聖二,他.
    • Organizer
      第25回日本がん分子標的治療学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Resistance to targeted therapy stratified with oncogenes or tumor suppressor genes.2021

    • Author(s)
      谷本 梓, 矢野聖二.
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Heterogeneity and drug resistance2021

    • Author(s)
      Seiji Yano
    • Organizer
      Wourld Conference on Lung Cancer 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Circumvention of targeted drug tolerance of lung cancer.2020

    • Author(s)
      矢野聖二
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 研究が切り拓く 肺がん治療の最前線2020

    • Author(s)
      矢野聖二
    • Organizer
      第36回日本癌学会市民公開講座
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Drug-tolerant persister cells and AXL.2019

    • Author(s)
      Yano S.
    • Organizer
      The 24th JFCR-ISCC
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Circumvention of targeted drug tolerance in lung cancer.2019

    • Author(s)
      Yano S.
    • Organizer
      International Symposium on Tumor Biology in Kanazawa 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Circumvention of targeted drug resistance in lung cancer.2019

    • Author(s)
      Yano S.
    • Organizer
      The Joint Symposium Microenvironment and Precision Oncology.
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Mechanism of the intrinsic resistance and emergence of tolerant cells to osimertinib in EGFR mutated lung cancer.2019

    • Author(s)
      Yano S.
    • Organizer
      11th AACR-JCA Joint Conference on Breakthroughs in Cancer Research: Biology to Precision Medicine.
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Circumvention of targeted drug tolerance in EGFR mutated lung cancer.2019

    • Author(s)
      矢野 聖二
    • Organizer
      第60回日本肺癌学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Mechanisms of drug tolerant cells to osimertinib in EGFR mutated lung cancer.2019

    • Author(s)
      矢野 聖二
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 肺がんの治療抵抗性メカニズムの最新情報.2019

    • Author(s)
      矢野 聖二
    • Organizer
      第23回日本がん分子標的治療学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Remarks] 金沢大学附属病院 がんセンター/金沢大学がん進展制御研究所 腫瘍内科

    • URL

      http://syuyounaika.w3.kanazawa-u.ac.jp/

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
  • [Remarks] 金沢大学附属病院がんセンター/金沢大学がん進展制御研究所腫瘍内科

    • URL

      http://syuyounaika.w3.kanazawa-u.ac.jp/

    • Related Report
      2019 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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