| Project/Area Number |
25860640
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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 |
Respiratory organ internal medicine
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| Research Institution | Kanazawa University |
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Principal Investigator |
TAKEUCHI Shinji 金沢大学, がん進展制御研究所, 助教 (90565384)
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| Project Period (FY) |
2013-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2013: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
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| Keywords | 肺癌 / EGFR変異 / アポトーシス / BIM遺伝子多型 / EGFR変異肺がん / BIM / HDAC阻害薬 / EGFR-TKI / apoptosis |
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| Outline of Final Research Achievements |
We investigated whether vorinostat, a histone deacetylase (HDAC) inhibitor, could circumvent EGFR-TKI resistance in the EGFR mutant lung cancer cell lines, which harbor the BIM polymorphism. We found that PC-3 cells with BIM polymorphism were much less sensitive to gefitinib-induced apoptosis than the EGFR mutant cell lines, which do not harbor this polymorphism. Vorinostat dose-dependently increased the expression of BIM with a pro-apoptotic BH3 domain and, together with gefitinib, induced apoptosis in cells with BIM polymorphism in vitro. In xenograft models, gefitinib did not induce regression of PC-3 subcutaneous tumors, whereas the combination of vorinostat and gefitinib induced marked regression of tumors, accompanied by tumor-cell apoptosis. These results indicate that the combination of HDAC inhibitor and EGFR-TKI may circumvent the resistance due to the BIM polymorphism in EGFR mutant lung cancer.
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