Journal
CANCER DISCOVERY
Volume 7, Issue 9, Pages 984-998Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-17-0419
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Funding
- National Health and Medical Research Council (NHMRC Australia) [1062702]
- Cancer Council Victoria
- Victorian Cancer Agency [CRF10-20, CRF16014]
- CRC for Cancer Therapeutics
- Stafford Fox Medical Research Foundation
- WEHI Centenary Stafford Fox Fellowship
- National Institutes of Health [2P50CA083636]
- Wendy Feuer Ovarian Cancer Research Fund
- Australian Cancer Research Foundation
- Victorian State Government Operational Infrastructure Support
- Australian Government NHMRC IRIISS
- Clovis Oncology
- V Foundation for Cancer Research
- Stand Up To Cancer Innovative Research Grant [SU2C-AACR-IRG-02-16]
- NIH [F32GM110978, R01CA185660]
- MSK Cancer Center Support Grant/Core Grant [NIH P30CA008748]
- Stand Up To Cancer-Ovarian Cancer Research Fund-Ovarian Cancer National Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant [SU2C-AACR-DT16-15]
- Victorian Life Sciences Computation Initiative [LTU0011]
- U. S. Army Medical Research and Materiel Command [DAMD17-01-10729]
- Cancer Council Tasmania
- Cancer Foundation of Western Australia
- National Health and Medical Research Council of Australia (NHMRC) [ID400413, ID400281]
- National Health and Medical Research Council of Australia [1062702] Funding Source: NHMRC
- MRC [G0601891] Funding Source: UKRI
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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. (C) 2017 AACR.
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