| Project/Area Number |
17K15507
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Medical pharmacy
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | EGFR / アファチニブ / オシメルチニブ / 肺癌 / 耐性 / EGFR-TKI / SRC / 薬剤耐性 / ダサチニブ / afatinib / osimertinib / Src family kinase |
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| Outline of Final Research Achievements |
Most non-small cell lung cancer patients with EGFR mutations benefit from treatment with EGFR-TKIs, but the clinical efficacy of second and third generation EGFR-TKIs is limited by the appearance of tumor drug resistance.
We characterized two independent resistant sublines, one selected by drug resistance to a second EGFR-TKI, afatinib, and also another selected by drug resistance to a third generation EGFR-TKI, osimertinib. These resistant sublines showed decreased expression of EGFR and increased expression of SRC family kinase (SFK). Treatment with SRC siRNA or an inhibitor of SFK blocked cell growth and Akt phosphorylation in them.
Together, the study presents SFK activation could be one key mechanism responsible for acquired drug resistance to EGFR-TKIs, also that combination with SFK-targeted drug could be useful to modify drug resistance to EGFR-TKIs.
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| Academic Significance and Societal Importance of the Research Achievements |
これまで肺癌治療には第1世代EGFR-TKIが広く使用されてきたが、現在臨床応用が広く進められてきている第2世代、第3世代EGFR-TKIに着目して新たな共通の耐性メカニズムを見出したことが本研究の大きな特徴である。今後、第2世代、第3世代EGFR-TKI 治療患者の耐性克服治療の創出及び、第2世代、第3世代EGFR-TKIを使用する際の適正化治療にも大きく貢献できると期待している。
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