Drug–gene Interaction Screens Coupled to Tumor Data Analyses Identify the Most Clinically Relevant Cancer Vulnerabilities Driving Sensitivity to PARP Inhibition

• DOI: 10.1158/2767-9764.crc-22-0119
• Publication Date: 2022-09-01T14:11:53Z
• Authors: Kunzah Jamal; Alessandro Galbiati; Joshua Armenia; Giuditta Illuzzi; James Hall; Sabrina Bentouati; Daniel Barrell; Miika Ahdesmäki; ; Mark J. O'Connor; Elisabetta Leo; Josep V. Forment
• Keywords: Olaparib; Synthetic Lethality; PARP inhibitor

PARP inhibitors (PARPi) are currently indicated for the treatment of ovarian, breast, pancreatic, and prostate cancers harboring mutations in tumor suppressor genes BRCA1 or BRCA2. In case ovarian cancers, their classification as homologous recombination repair (HRR) deficient (HRD) mutated also makes PARPi an available option beyond BRCA2 mutational status. However, identification most relevant genetic alterations driving HRD phenotype has proven difficult recent data have shown that other not affecting HRR capable responses. To gain insight into genetics sensitivity, we performed CRISPR-Cas9 loss-of-function screens six PARPi-insensitive cell lines combined output with published datasets from eight additional lines. Ensuing exploration identified 110 whose inactivation is strongly linked to sensitivity PARPi. Parallel line generation isogenic gene knockouts cancer core factors required vitro responses comparable ones observed mutations. Moreover, pan-cancer genetic, transcriptomic, epigenetic analyses these highlight frequently inactivated tumors, making this study a valuable resource prospective potential PARPi-responsive patient populations. Importantly, our investigations uncover XRCC3 silencing new prognostic biomarker cancer.This identifies backgrounds where expand use PARPis This achieved by combining unbiased genome-wide bioinformatics analysis biallelic losses public datasets, unveiling loss DNA cancer.