BRCA1185delAG results in expression of mutant BRCA1 lacking the RING domain, promoting resistance.
Major finding: BRCA1185delAG results in expression of mutant BRCA1 lacking the RING domain, promoting resistance.
Concept: Acquired resistance in BRCA1185delAG tumors develops independent of secondary reversion mutations.
Impact: RING-less BRCA1 expression may predict response to therapy in patients with BRCA1-mutant tumors.
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 BRCA1185delAG, 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 BRCA1185delAG 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 BRCA1185delAG 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 BRCA1185delAG tumors. Heterogeneous responses to platinum drugs and PARP inhibitors suggest that BRCA1 mutations may have differing effects. Drost and colleagues investigated the role of BRCA1185delAG and a second common BRCA1 mutation, BRCA15382insC, in acquired therapeutic resistance using genetically engineered mouse models. Both mutations increased the susceptibility to mammary tumors; however, the RING-less BRCA1185delAG mutation resulted in a poorer response to cisplatin and PARP inhibition, and more rapid development of resistance than BRCA15382insC. 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.