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Updated: Mar 1, 2026
Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays
Published on: February 24, 2023
Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor
Olga Kondrashova1,2, Minh Nguyen3, Kristy Shield-Artin1,2
1Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Abstract:
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 RAD51CIn 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. 937See related article by Quigley et al., p. 999See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920.
Insights
Secondary mutations in RAD51C and RAD51D can restore homologous recombination function, leading to acquired resistance to PARP inhibitors (PARPi) in ovarian cancer. This highlights the need for timely PARPi treatment and combination strategies.
Area of Science:
- Genomics
- Oncology
- Molecular Biology
Background:
- High-grade epithelial ovarian carcinomas with BRCA1/2 mutations are sensitive to platinum chemotherapy and PARP inhibitors (PARPi).
- Restoration of homologous recombination (HR) function via secondary BRCA1/2 mutations is a known resistance mechanism.
Purpose of the Study:
- To investigate primary and secondary mutations in HR pathway genes in patients with platinum-sensitive, relapsed ovarian carcinoma treated with the PARPi rucaparib.
- To determine the role of secondary mutations in acquired resistance to PARPi therapy.
Main Methods:
- Sequencing of core HR pathway genes in 12 paired pretreatment and postprogression tumor biopsies from the ARIEL2 Part 1 study.
- In vitro complementation assays, patient-derived xenograft models, and molecular modeling to assess resistance mechanisms.
Main Results:
- Truncation mutations in BRCA1, RAD51C, or RAD51D were found in 6 of 12 pretreatment biopsies.
- Five of six paired postprogression biopsies showed secondary mutations restoring the open reading frame, including four distinct mutations in RAD51C.
- Secondary mutations were confirmed to cause resistance to rucaparib.
Conclusions:
- Primary mutations in RAD51C and RAD51D confer sensitivity to PARPi.
- Secondary mutations in these genes represent a mechanism of acquired PARPi resistance in ovarian cancer.
- The findings underscore the importance of early PARPi administration and combination therapies.
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