Abstract PR014: Genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer

Abstract

Abstract Prostate cancer (PCa) patients harboring BRCA1/2 mutations are often sensitive to PARP inhibition. However, genomic alterations in other DNA damage response (DDR) genes have not been consistently predictive of clinical response to PARP inhibition. In this study, we preformed genome-wide CRISPR/Cas9 loss-of-function screens in four BRCA-proficient PCa cell lines with the goal of expanding the use of PARP inhibitors (PARPis) beyond BRCA1/2 mutations and finding new synthetically lethal interactions. We provided a systematic view of the genetic determinants and mechanisms underlying PARPi sensitivity and resistance in PCa beyond BRCA1/2 alterations. We identified previously unknown genes whose loss has a profound impact on PARPi response, serving as new predictive biomarkers for PARP inhibition if mutated or deleted in PCa or therapeutic targets through pharmacologic inhibition in combination with PARPis. Specifically, we discovered two genes RNASEH2B and MMS22L, located on frequently deleted genomic regions on chromosomes 13q (up to 17%) and 6q (up to 14%) respectively in PCa, loss of which confers BRCA-like synthetic lethality to PARP inhibition. On the other hand, we found that inactivation of TP53 and RB1, two commonly mutated tumor suppressor genes in PCa, may compromise PARP inhibitor response. Mechanistically, loss of RNASEH2B confers PCa cells sensitivity to PARP inhibition due to impaired ribonucleotide excision repair and PARP trapping. When co-deleted with RB1 on the same genomic region, however, cells lose their sensitivity, in part, through E2F1-induced BRCA2 expression, thereby enhancing homologous recombination repair (HRR) capacity. Loss of MMS22L renders PCa cells hypersensitive to PARP inhibition by disrupting RAD51 loading required for HRR. However, this response is TP53-dependent. Inactivation of TP53 renders cells resistant to PARPis through increased BRCA2 expression, a target of TP53-E2F7 mediated transcriptional repression. Our findings may inform the use of PARPi beyond BRCA1/2-deficient tumors, but also indicate that current biomarkers guided by mutations of a single gene overlook concurrent genomic alterations.These results may explain some of the disparate clinical results from PARP inhibition due to interaction between multiple genomic alterations and support a comprehensive genomic testing to determine who may benefit from PARP inhibition. In addition, we found that loss of CHEK2 confers resistance rather than sensitivity to PARP inhibition through increased expression of BRCA2, which enhances HRR capacity sufficient for the repair of PARPi-induced double-strand DNA breaks and cell survival. Combined PARP and ATR inhibition overcomes PARPi resistance caused by CHEK2 loss. Our findings support reevaluation of current biomarkers for PARP inhibition in PCa treatment. Citation Format: Takuya Tsujino, Tomoaki Takai, Chenkui Miao, Fu Gui, Adam S. Kibel, Li Jia. Genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR014.