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

• 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: ¥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.

Research Products

• [Journal Article] Survivin knockdown induces senescence in TTF-1-expressing, KRAS-mutant lung adenocarcinomas. (2018)
  • Author(s): Sumi T, Hirai S, Yamaguchi M, Tanaka Y, Tada M, Yamada G, Hasegawa T, Miyagi Y, Niki T, Watanabe A, Takahashi H, Sakuma Y.
  • Journal Title: International Journal of Oncology Volume: 52 Pages: 33-46
  • DOI: 10.3892/ijo.2018.4365
  • Peer Reviewed / Open Access
• [Presentation] Kras変異陽性肺腺癌におけるsurvivinの治療標的分子としての基礎的検討 (2017)
  • Author(s): 角俊行、田中悠祐、平井幸恵、山口美樹、山田玄、渡辺敦、高橋弘毅、佐久間裕司
  • Organizer: 第58回日本肺癌学会総会