Abstract 391: Identifying molecular drivers of olaparib resistance through genome-wide sgRNA screening in prostate organoids

Abstract Cancers harboring bi-allelic loss of the breast cancer genes (BRCA1 and BRCA2) are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPi), which are clinically approved in breast, ovarian, and more recently prostate cancer. Genetic alteration of BRCA2 is frequent in metastatic castration-resistant prostate cancer (mCRPC), and confers sensitivity to the PARPi olaparib; however, resistance is anticipated. mCRPC has a unique genetic landscape, and is likely to present different mechanisms of resistance compared to breast and ovarian cancer because loss of BRCA2 in prostate cancer occurs primarily through a large deletion of 13q that frequently includes Rb1; a setting in which reversion mutations of Brca2 are not possible. We have developed Brca2-deficient olaparib-sensitive murine prostate organoid models in clinically relevant genetic backgrounds (Brca2∆/∆Trp53∆/∆Pten∆/∆, Brca2∆/∆Trp53∆/∆, and Brca2∆/∆ sgRb1), as well as cell lines and patient-derived xenografts (PDX) to identify molecular mechanisms of olaparib resistance. We employed a genome-wide sgRNA positive selection screen to identify gene drivers of olaparib resistance in Brca2-deficient murine prostate organoid models. Putative resistance drivers are involved in many relevant pathways including DNA replication and repair, PARP1 substrate NAD+ metabolism, and androgen receptor signaling. While some pathways are genotype-specific, some are driving resistance in a pan-genotype manner. We are currently using our olaparib-sensitive model systems to validate specific resistance drivers in vitro and in vivo, determine their specificity to the BRCA1 or BRCA2 loss settings, and unravel the precise molecular mechanisms behind these resistance drivers. Citation Format: Kyrie Jean Pappas, Wouter Karthaus, Justin Laclair, Marco Russo, Charles Sawyers. Identifying molecular drivers of olaparib resistance through genome-wide sgRNA screening in prostate organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 391.