Abstract 6394: Combined FLT3 and PARP inhibition induces synthetic lethality in non-small cell lung cancer cells

Abstract

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Fms-like receptor tyrosine kinase 3 (FLT3), a member of class III receptor tyrosine kinase, targeted inhibitors have not been well studied in lung cancer including NSCLC. Since recent studies have been reported that FLT3 inhibitors can suppress DNA repair activities, we investigated the antitumor activities of quizartinib, an FLT3 inhibitor, in NSCLC cells to expand the use of FLT3 inhibitors. Quizartinib inhibited the growth of NSCLC cells in a concentration-dependent manner, and induced DNA damage and reactive oxygen species (ROS) generation in A549 and H1299 cells. We found that quizartinib suppressed DNA damage repair genes through the downregulation of STAT5, resulting in the ‘BRCAness' or ‘DNA-PKness' phenotype in A549 and H1299 cells. As quizartinib-induced ‘BRCAness/DNA-PKness' and poly(ADP-ribose) polymerase inhibitors (PARP) inhibition can induce synthetic lethality, combined treatment with quizartinib and olaparib, a PARP inhibitor, showed synergistic inhibitory proliferation and apoptotic cell death in A549 and H1299 cells compared with either drug alone. Taken together, our findings suggest that quizartinib may be a synthetic lethal partner of PARP inhibitors to enhance therapeutic efficacy in NSCLC cells. Citation Format: Hwani Ryu, Hyo Jeong Kim, Jie-Young Song, Sang-Gu Hwang, Jiyeon Ahn. Combined FLT3 and PARP inhibition induces synthetic lethality in non-small cell lung cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6394.