RT Journal Article SR Electronic T1 Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma JF Cancer Discovery JO Cancer Discov FD American Association for Cancer Research SP 984 OP 998 DO 10.1158/2159-8290.CD-17-0419 VO 7 IS 9 A1 Kondrashova, Olga A1 Nguyen, Minh A1 Shield-Artin, Kristy A1 Tinker, Anna V. A1 Teng, Nelson N.H. A1 Harrell, Maria I. A1 Kuiper, Michael J. A1 Ho, Gwo-Yaw A1 Barker, Holly A1 Jasin, Maria A1 Prakash, Rohit A1 Kass, Elizabeth M. A1 Sullivan, Meghan R. A1 Brunette, Gregory J. A1 Bernstein, Kara A. A1 Coleman, Robert L. A1 Floquet, Anne A1 Friedlander, Michael A1 Kichenadasse, Ganessan A1 O'Malley, David M. A1 Oza, Amit A1 Sun, James A1 Robillard, Liliane A1 Maloney, Lara A1 Bowtell, David A1 Giordano, Heidi A1 Wakefield, Matthew J. A1 Kaufmann, Scott H. A1 Simmons, Andrew D. A1 Harding, Thomas C. A1 Raponi, Mitch A1 McNeish, Iain A. A1 Swisher, Elizabeth M. A1 Lin, Kevin K. A1 Scott, Clare L. YR 2017 UL http://cancerdiscovery.aacrjournals.org/content/7/9/984.abstract AB High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 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 BRCA1, RAD51C, or RAD51D 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 RAD51C. In vitro complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations.Significance: Analyses of primary and secondary mutations in RAD51C and RAD51D 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. Cancer Discov; 7(9); 984–98. ©2017 AACR.See related commentary by Domchek, p. 937.See related article by Quigley et al., p. 999.See related article by Goodall et al., p. 1006.This article is highlighted in the In This Issue feature, p. 920