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Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer
Open accessAbstract
Approximately 50% of epithelial ovarian cancers (EOC) exhibit defective DNA repair via homologous recombination (HR) due to genetic and epigenetic alterations of HR pathway genes. Defective HR is an important therapeutic target in EOC as exemplified by the efficacy of platinum analogues in this disease, as well as the advent of PARP inhibitors, which exhibit synthetic lethality when applied to HR-deficient cells. Here, we describe the genotypic and phenotypic characteristics of HR-deficient EOCs, discuss current and emerging approaches for targeting these tumors, and present challenges associated with these approaches, focusing on development and overcoming resistance. Significance: Defective DNA repair via HR is a pivotal vulnerability of EOC, particularly of the high-grade serous histologic subtype. Targeting defective HR offers the unique opportunity of exploiting molecular differences between tumor and normal cells, thereby inducing cancer-specific synthetic lethality; the promise and challenges of these approaches in ovarian cancer are discussed in this review. Cancer Discov; 5(11); 1137–54. ©2015 AACR.
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“Increasing evidence suggests that tumors with HR deficiency are more likely to be highly sensitive to platinum-based chemotherapy20–22.”
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Colombo, N., Sessa, C., du Bois, A., Ledermann, J., McCluggage, W. G., McNeish, I., Morice, P., Pignata, S., Ray-Coquard, I., Vergote, I., et al. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz062 · Cited by 1,197
Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer
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A decade of clinical development of PARP inhibitors in perspective
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“Numerous mechanisms of acquired resistance to PARPi have been described in pre-clinical and clinical studies [65, 66]; these can be grouped into three main classes (Figure 2).”
BackgroundTargeting DNA Repair in Cancer: Beyond PARP Inhibitors
Brown, J. S., O’Carrigan, B., Jackson, S. P., & Yap, T. A. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0860 · Cited by 642
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Self-citation
Metadata
- Authors
- Konstantinopoulos, P. A., Ceccaldi, R., Shapiro, G. I., & D'Andrea, A. D.
- Affiliations
- Harvard University (US)
- 2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
- Corresponding author
- Konstantinopoulos, Panagiotis A.
- Venue
- Cancer Discovery
- Published
- 2015-11-01
- Volume
- 5
- Issue
- 11
- Pages
- 1137-1154
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4631624
- OpenAlex
- W2179105349
- Cited by
- 945
- References
- 180
- Citations by year
- 2026: 67 · 2025: 97 · 2024: 109 · 2023: 126 · 2022: 115 · 2021: 102 · 2020: 100 · 2019: 74 · 2018: 74 · 2017: 54 · 2016: 27
- FWCI
- 5.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA090687, UM1CA186709, P50CA168504)
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
- Keywords
- homologous recombination deficiency, epithelial ovarian cancer, DNA repair deficiency, PARP inhibitors, synthetic lethality, platinum analogues, high-grade serous ovarian cancer, drug resistance, targeted therapy
- MeSH terms
- Carcinoma, Ovarian Epithelial, Animals, Antineoplastic Combined Chemotherapy Protocols, Clinical Trials as Topic, DNA Repair, Female, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Phenotype, Genetic Variation, Signal Transduction, Biomarkers, Gene Expression Regulation, Neoplastic, Treatment Outcome, Drug Resistance, Neoplasm, Molecular Targeted Therapy, Homologous Recombination
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