PBRM1 deficiency in cancer is synthetic lethal with DNA repair inhibitors

Polybromo 1 (PBRM1), a subunit of the PBAF chromatin-remodeling complex, is recurrently inactivated in cancer. To uncover novel synthetic lethal (SL) approaches for targeting PBRM1-defective cancers, we used a series of orthogonal functional genomic screens which identified SL between PBRM1 deficiency and inhibition of PARP1. This effect was elicited with clinical PARP inhibitors in vitro and in vivo and also operated when PARP inhibitors were combined with ATR inhibitors. These SL effects were characterized by pre-existing replication stress in PBRM1-defective cells and an increase in R-loops, micronuclei and tumor cell-autonomous cGAS/STING signaling in response to PARP inhibitors. Quantitative mass spectrometry indicated that PBRM1-defective cells exhibited downregulation of multiple R-loop processing factors, and exogenous expression of the R-loop resolution enzyme RNase H1 partially reversed PARP inhibitor sensitivity, providing a mechanistic rationale for the SL effects. Our data provide the preclinical basis for using PARP inhibitors in PBRM1-defective cancers.