RING-less BRCA1 Induces PARP Inhibitor and Platinum Resistance

Germline mutations in BRCA1 increase the risk of developing breast and ovarian cancers. BRCA1 is involved in DNA double-strand break (DSB) repair by homologous recombination (HR), and patients with BRCA1-mutant tumors initially respond well to platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors, but eventually develop resistance. Wang and colleagues investigated resistance mechanisms associated with BRCA1^185delAG, a common inherited mutation thought to produce a truncated, nonfunctional peptide. In a cell line derived from a patient with invasive ductal carcinoma with the BRCA1^185delAG mutation, treatment with a PARP inhibitor or cisplatin resulted in acquired resistance, but was not associated with secondary reversion mutations, a mechanism previously associated with platinum resistance. Moreover, the BRCA1^185delAG mutation resulted in expression of BRCA1 lacking the N-terminal RING domain (RING-less), a domain found in E3 ubiquitin ligases. Functionally, expression of RING-less BRCA1 induced resistance to cisplatin and PARP inhibition in tumor xenografts, and RING-less BRCA1 was expressed in patients with resistant BRCA1^185delAG tumors. Heterogeneous responses to platinum drugs and PARP inhibitors suggest that BRCA1 mutations may have differing effects. Drost and colleagues investigated the role of BRCA1^185delAG and a second common BRCA1 mutation, BRCA1^5382insC, in acquired therapeutic resistance using genetically engineered mouse models. Both mutations increased the susceptibility to mammary tumors; however, the RING-less BRCA1^185delAG mutation resulted in a poorer response to cisplatin and PARP inhibition, and more rapid development of resistance than BRCA1^5382insC. RING-less BRCA1 promoted DNA repair by HR, thereby reducing sensitivity to cisplatin and PARP inhibition. Further, in patient-derived xenografts, expression of RING-less BRCA1 was associated with reduced sensitivity to PARP inhibition. Taken together, these studies indicate that mutations resulting in expression of RING-less BRCA1 can promote resistance to platinum chemotherapy and PARP inhibition, and suggest that expression of RING-less BRCA1 may serve as a biomarker to predict response to therapy in patients with BRCA1-mutant tumors.

Wang Y, Krais JJ, Bernhardy AJ, Nicolas E, Cai KQ, Harrell MI, et al. RING domain-deficient BRCA1 promotes PARP inhibitor and platinum resistance. J Clin Invest 2016;126:3145–57.

Drost R, Dhillon KK, van der Gulden H, van der Heijden I, Brandsma I, Cruz C, et al. BRCA1^185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1. J Clin Invest 2016;126:2903–18.