Secondary Somatic Mutations Restoring <i>RAD51C</i> and <i>RAD51D</i> Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

High-grade epithelial ovarian carcinomas containing mutated <i>BRCA1</i> or <i>BRCA2</i> (<i>BRCA1/2</i>) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due to secondary mutations in <i>BRCA1/2</i> has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in <i>BRCA1, RAD51C</i>, or <i>RAD51D</i> was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for <i>RAD51C</i><i>In vitro</i> complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations.<b>Significance:</b> Analyses of primary and secondary mutations in <i>RAD51C</i> and <i>RAD51D</i> provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies. <i>Cancer Discov; 7(9); 984-98. ©2017 AACR.</i><i>See related commentary by Domchek, p. 937</i><i>See related article by Quigley et al., p. 999</i><i>See related article by Goodall et al., p. 1006</i><i>This article is highlighted in the In This Issue feature, p. 920</i>.