Loss of E2F7 confers resistance to poly-ADP-ribose polymerase (PARP) inhibitors in BRCA2-deficient cells

Abstract

BRCA proteins are essential for Homologous Recombination DNA repair, and their germline or somatic inactivation is frequently observed in human tumors. Understanding the molecular mechanisms underlying the response to chemotherapy of BRCA-deficient tumors is paramount for developing improved personalized cancer therapies. While PARP inhibitors have been recently approved for treatment of BRCA-mutant breast and ovarian cancers, resistance to these novel drugs remains a major clinical problem. Several mechanisms of chemoresistance in BRCA2-deficient cells have been identified. Rather than restoring normal recombination, these mechanisms result in stabilization of stalled replication forks, which normally are subjected to degradation in BRCA2-mutated cells. Here, we show that the transcriptional repressor E2F7 controls chemoresistance in BRCA2-deficient cells. We found that E2F7 depletion restores PARP inhibitor and cisplatin resistance in BRCA2-depleted cells. Moreover, we show that the mechanism underlying this activity involves increased expression of RAD51, a target for E2F7-mediated transcriptional repression, which enhances both Homologous Recombination DNA repair, and replication fork stability in BRCA2-deficient cells. Our work describes a new mechanism of chemotherapy resistance in BRCA2-deficient cells, and identifies E2F7 as a novel biomarker for tumor response to PARP inhibitor therapy.