RT Journal Article
SR Electronic
T1 Secondary Somatic Mutations Restoring <em>RAD51C</em> and <em>RAD51D</em> 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