Study to circumvent targeted drug resistance in leptomeningeal carcinomatosis of lung cancer
| Project/Area Number |
16H05308
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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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| Research Field |
Respiratory organ internal medicine
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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) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2016: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
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| Keywords | 分子標的薬耐性 / 髄膜がん腫症 / EGFR-TKI / 髄膜がん種症 / 耐性変異 / 中枢神経系転移 / ALK阻害薬耐性 / NTRK1融合遺伝子陽性がん |
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| Outline of Final Research Achievements |
In the leptomeningeal carcinomatosis (LMC) model of EGFR mutated lung cancer, we demonstrated that MET copy number gain caused resistance to 1st generation EGFR-tyrosine kinase inhibitors (TKI) and that combined use of MET inhibitor overcame the resistance. We also discovered 2 mutations which caused resistance to 3rd generation EGFR-TKI, osimertinib, in the LMC model. In the LMC model of ALK-rearranged lung cancer, we found that amphiregulin, an EGFR ligand, induced resistance to ALK-TKI alectinib and that combined use of EGFR-TKI overcame the resistance. In the brain metastasis model of NTRK1-rearranged cancer, we showed that NTRK1-G667C mutation caused resistance to TRK-A inhibitor entrectinib and that foretinib circumvent the resistance.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究において、肺がんの髄膜がん腫症における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。
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Report
(4 results)
Research Products
(30 results)
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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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[Journal Article] Foretinib overcomes entrectinib resistance associated with the NTRK1 G667C mutation in NTRK1 fusion-positive tumor cells in a brain metastasis model.2018
Author(s)
22.Nishiyama A, Yamada T, Kita K, Wang R, Arai S, Fukuda K, Tanimoto A, Takeuchi S, Tange S, Tajima A, Furuya N, Kinoshita T, Yano S.
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Journal Title
Clinical Cancer Research
Volume: [Epub ahead of print]
Related Report
Peer Reviewed
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[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.
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Journal Title
Cancer Sci.
Volume: 108
Issue: 4
Pages: 696-703
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
Cancer Med
Volume: 6
Issue: 12
Pages: 2972-2983
DOI
Related Report
Peer Reviewed / Open Access
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