Basic examination of survivin as therapeutic targets in KRAS-mutant lung adenocarcinoma

Research Project

Project/Area Number	16K19459
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Respiratory organ internal medicine
Research Institution	Sapporo Medical University
Principal Investigator	SUMI Toshiyuki 札幌医科大学, 医学部, 研究員 (60772291)
Research Collaborator	HIRAI sachie YAMAGUCHI miki TANAKA yusuke TADA makoto YAMADA gen HASEGAWA tadashi MIYAGI yohei NIKI toshiro WATANABE atsushi TAKAHASHI hiroki SAKUMA yuji
Project Period (FY)	2016-04-01 – 2018-03-31
Project Status	Completed (Fiscal Year 2017)
Budget Amount *help	¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000) Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000) Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords	KRAS / survivin / trametinib / ABT-263 / TTF-1 / 肺腺癌 / Kras変異
Outline of Final Research Achievements	Survivin is highly expressed in the majority of malignant tumors. However, little is known about the roles of survivin in KRAS-mutant lung adenocarcinomas. In the present study, we examined 28 KRAS-mutant lung adenocarcinoma tissues and two KRAS-mutant lung adenocarcinoma cell lines, H358 and H441, in order to elucidate the potential of survivin as a therapeutic target. Patients with tumors immunohistochemically positive for survivin (n=18) had poorer outcomes than those with survivin-negative tumors (n=10). In the H358 and H441 cells, survivin knockdown alone induced senescence, not apoptosis. However, the H358 cells and H441 cells in which survivin was silenced, underwent significant apoptosis following combined treatment with ABT-263, a Bcl-2 inhibitor, and trametinib, a MEK inhibitor. Importantly, the triple combination of survivin knockdown with ABT-263 and trametinib treatment, clearly induced cell deathin an in vivo tumor xenograft model.