Cited by 946PARP inhibition in cancer therapyBRCA gene mutations in cancerOvarian cancer diagnosis and treatment

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Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer

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Konstantinopoulos, Panagiotis A., Ceccaldi, Raphael, Shapiro, Geoffrey I., D'Andrea, Alan D.·2015·Cancer Discovery

DOI 10.1158/2159-8290.cd-15-0714PMC PMC4631624

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Abstract

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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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.
ORCID: Konstantinopoulos, Panagiotis A.
Shapiro, Geoffrey I.
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2015-11-01
Volume: 5
Issue: 11
Pages: 1137-1154
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-15-0714
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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Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer

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