Abstract 1694: Loss ofZNF251stimulates NHEJ resulting in PARP inhibitor resistance inBRCA1-mutated cancer cells

Abstract

Abstract The poly (ADP-ribose) polymerases (PARPs) inhibitors are an exciting new class of agents that have shown efficacy in treating various cancers, especially those harboring BRCA1/2 mutations. The cancer associated BRCA1/2mutations disrupt DNA double strand break (DSB) repair by homologous recombination (HR). PARP inhibitors (PARPi) have been applied to trigger synthetic lethality in BRCA1/2-mutated cancer cells by promoting the accumulation of toxic DSBs. Unfortunately, PARPi resistance is common and develops through multiple mechanisms. Restoring HR and/or stabilizing replication forks are two major mechanisms of PARPi resistance in BRCA1/2-mutated cells. To further understand the mechanisms of drug resistance to PARPi, we took an unbiased approach with a CRISPR-pooled genome-wide library to screen new genes whose loss-of-function confers resistance to PARPi olaparib. We identified ZNF251, a transcription factor, and found that its loss-of-function led to the PARPi resistance in multipleBRCA1-mutated breast and ovarian cancer lines. Elevated activities of both HR and non-homologous end joining (NHEJ) repair were detected in cancer cells harboring BRCA1 mutation and ZNF251 deletion (BRCA1mut+ZNF251del) and were associated with enhanced expression of RAD51 and Ku70/Ku80, respectively. Furthermore, we showed that a DNA-PKcs inhibitor restored sensitivity of BRCA1mut+ZNF251del cells to PARPi ex vivo and in vivo. Taken together, our study discovered a novel gene ZNF251 whose loss-of-function conferred resistance to PARPi in BRCA1-mutated breast and ovarian cancers and identified DNA repair pathway responsible for this effect. Citation Format: Jian Huang, Tomasz Skorski. Loss ofZNF251stimulates NHEJ resulting in PARP inhibitor resistance inBRCA1-mutated cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1694.