Development of therapy for circumvention of EGFR-TKI resistance due to BIM polymorphism in EGFR mutant lung cancer.

2014 Fiscal Year Final Research Report

• Project/Area Number: 25860640
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Kanazawa University
• Principal Investigator: TAKEUCHI Shinji 金沢大学, がん進展制御研究所, 助教 (90565384)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 肺癌 / EGFR変異 / アポトーシス / BIM遺伝子多型

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.

Free Research Field

呼吸器内科、腫瘍内科