Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer

Cancer Discov. 2015 Nov;5(11):1137-54. doi: 10.1158/2159-8290.CD-15-0714. Epub 2015 Oct 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers
  • Carcinoma, Ovarian Epithelial
  • Clinical Trials as Topic
  • DNA Repair
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genetic Variation
  • Homologous Recombination*
  • Humans
  • Molecular Targeted Therapy
  • Neoplasms, Glandular and Epithelial / genetics
  • Neoplasms, Glandular and Epithelial / metabolism
  • Neoplasms, Glandular and Epithelial / pathology
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Phenotype
  • Signal Transduction / drug effects
  • Treatment Outcome


  • Biomarkers