Abstract AP13: GENOME-SCALE CRISPR KNOCKOUT SCREEN IDENTIFIES TIGAR AS A MODIFIER OF PARP INHIBITOR SENSITIVITY

Abstract

A key challenge is to understand the mechanisms that contribute to “BRCAness” and hence sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. Using the sensitivity to PARP inhibitor olaparib as a surrogate for “BRCAness”, we performed a CRISPR/Cas9-based genome-scale loss-of-function screen and identified TIGAR as a modifier of olaparib response. TIGAR knockdown increases the level of intracellular reactive oxygen species, induces more DNA damage after olaparib treatment, and causes “BRCAness” by downregulating BRCA1 and genes in the Fanconi anemia pathway. Further, TIGAR knockdown induces senescence, reduces spheroid tumor cell growth, and enhances the cytotoxic effect of olaparib. Finally, TIGAR is amplified in ovarian cancer and a higher expression of TIGAR is associated with poor overall survival in high-grade serous ovarian cancer. Our study shows that TIGAR knockdown causes extensive transcriptional reprogramming and enhances sensitivity to PARP inhibitor, demonstrating that TIGAR is a relevant therapeutic target for treating ovarian cancer. Citation Format: Pingping Fang, Kay Minn, Jeremy Chien. GENOME-SCALE CRISPR KNOCKOUT SCREEN IDENTIFIES TIGAR AS A MODIFIER OF PARP INHIBITOR SENSITIVITY [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP13.