CRISPR screening identifies novel PARP inhibitor classification based on distinct base excision repair pathway dependencies

DNA repair deficiencies have become an increasingly promising target for novel therapeutics within the realm of clinical oncology. Recently, a number of inhibitors of Poly(ADP-ribose) Polymerases (PARPs) have received approval for the treatment of ovarian cancers with and without deleterious mutations in the homologous recombination proteins BRCA1 and BRCA2. Unfortunately, as over two hundred clinical trials are actively underway testing the utility of PARP inhibition across dozens of unique cancers, the mechanism of action for such inhibitors remains unclear. While many believe PARP trapping to be the most important factor in the cytotoxicity found in such inhibitors, clinically effective inhibitors exist across the entirety of this spectrum. Such results indicate that classification of inhibitors as strong and weak trappers does not properly capture the intra-class characteristics of such small molecule inhibitors. Using a novel, targeted DNA damage repair and response (DDR) CRISPR/Cas9 screening library, we describe a new classification scheme for PARP inhibitors that revolves around sensitivity to key modulators of the base excision repair (BER) pathway, unrelated to trapping ability or catalytic inhibition of PARP. These findings, described within, show that inhibition of PARylation and induction of PARP trapping are not the only factors at play in the response to PARP inhibitors in DDR-deficient cancers, and may provide insight into choice of PARP inhibition in the setting of additional DNA repair deficiencies.