| Project/Area Number |
16K18461
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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 |
Tumor therapeutics
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| Research Institution | Kindai University |
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Principal Investigator |
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| Research Collaborator |
WATANABE satomi
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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 |
¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
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| Keywords | 非小細胞肺癌 / 分子標的治療 / 薬剤耐性 / EGFR阻害薬 / プロテオミクス |
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| Outline of Final Research Achievements |
We evaluated the efficacy of dasatinib combined with the T790M-selective EGFR-TKI ASP8273 or osimertinib in EGFR mutation-positive NSCLC with or T790M mutation. A cell viability assay revealed that dasatinib had synergistic effects with these TKIs in T790M-positive cells and simultaneously inhibited Src, Akt, and Erk, which remained activated upon single-agent treatment. Dasatinib also increased the rate of apoptosis in T790M-positive cells induced by T790M-selective EGFR-TKIs, as determined by the Annexin-V binding assay; this was associated with downregulation of the antiapoptotic Bcl-2 family member Bcl-xL, a finding that was confirmed in mice bearing T790M-positive xenografts. Our results suggest that Bcl-xL plays a key role in the apoptosis resistance of T790M-positive NSCLC, and that dasatinib combined with clinically relevant T790M-selective EGFR-TKIs is potentially effective in overcoming resistance to first-generation EGFR-TKIs in NSCLC patients with acquired T790M.
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| Academic Significance and Societal Importance of the Research Achievements |
EGFR陽性非小細胞肺癌に対してはEGFR-TKIが著効するがT790M遺伝子による獲得耐性が臨床的な問題となっている。我々は以前の研究でSrcがT790M存在下におけるco-driverとして重要であることを確認した。また本課題において実際にT790M選択的EGFR-TKIとSrc阻害薬ダサチニブの併用効果をT790M陽性非小細胞肺癌細胞株および、これを皮下移植したマウスモデルにおいて証明したことで、本併用療法がEGFR-TKI耐性非小細胞肺癌患者への治療戦略となり得る可能性があり、今後の臨床応用が期待される。
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