<i>RB1</i> loss overrides PARP inhibitor sensitivity driven by <i>RNASEH2B</i> loss in prostate cancer

Abstract

Current targeted cancer therapies are largely guided by mutations of a single gene, which overlooks concurrent genomic alterations. Here, we show that <i>RNASEH2B</i>, <i>RB1</i>, and <i>BRCA2</i>, three closely located genes on chromosome 13q, are frequently deleted in prostate cancer individually or jointly. Loss of <i>RNASEH2B</i> confers cancer cells sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to impaired ribonucleotide excision repair and PARP trapping. When co-deleted with <i>RB1</i>, however, cells lose their sensitivity, in part, through E2F1-induced BRCA2 expression, thereby enhancing homologous recombination repair capacity. Nevertheless, loss of <i>BRCA2</i> resensitizes <i>RNASEH2B/RB1</i> co-deleted cells to PARP inhibition. Our results may explain some of the disparate clinical results from PARP inhibition due to interaction between multiple genomic alterations and support a comprehensive genomic test to determine who may benefit from PARP inhibition. Last, we show that ATR inhibition can disrupt E2F1-induced BRCA2 expression and overcome PARP inhibitor resistance caused by <i>RB1</i> loss.