Development of synthetic lethality on lung cancer harboring KRAS mutation

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10670
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory surgery
• Research Institution: Tohoku University
• Principal Investigator: Sakurada Akira 東北大学, 加齢医学研究所, 准教授 (60360872)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 肺癌 / 腺癌 / KRAS / 合成致死

Outline of Final Research Achievements

Synthetic lethality on lung cancer cells harboring KRAS gene mutation was tested. p190RhoGAP was assumed as one target and additional targets were intended to identify by using isogenic cell culture model in combination with siRNA library screening. As integration of autofluorescent gene was unstable, we switched isogenic model to combination of inhibitors. We confirmed that inhibition of Src, a upstream regulator of p190RhoGAP, strongly donuregulates p190RhoGAP activity. Then, we identified that Stat3 was upregulated and contributed for cell survival after stale knock down of p190RhoGAP. We demonstarated that simultaneous inhibiton ofStat3 and SRC synergistically supress cell proliferation of A549 cell.

Free Research Field

呼吸器外科

Academic Significance and Societal Importance of the Research Achievements

今回、KRAS遺伝子変異を有する肺癌細胞株を用いた実験で、SRC阻害薬とSTAT3の阻害薬がいずれも増殖抑制効果を示すこと、また、両者を併用すると相乗的で強力な細胞増殖抑制効果が得られることを示した。肺癌の分子標的治療は進歩しているが、これまでKRAS遺伝子変異を有する肺癌に対しては有効な治療法が確立しておらず、今回の結果は新たな治療の可能性を示すものと考えられる。