Formation of a non-clinical research base for treatment aimed to eradicate lung cancer by targeted drugs
| Project/Area Number |
19H03665
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 53030:Respiratory medicine-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
Yano Seiji 金沢大学, がん進展制御研究所, 教授 (30294672)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| 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)
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| 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 |
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| 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。
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| 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.
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| 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。
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Report
(4 results)
Research Products
(30 results)
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[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.
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Journal Title
NPJ Precis Oncol
Volume: 6
Issue: 1
Pages: 11-11
DOI
Related Report
Peer Reviewed / Open Access
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[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
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Journal Title
Cancer Science
Volume: 110(10)
Issue: 10
Pages: 3215-3224
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
Nat Commun.
Volume: 10
Issue: 1
Pages: 259-259
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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