title: Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Oncology, Medical Gynecologic Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. alan_dandrea@dfci.harvard.edu panagiotis_konstantinopoulos@dfci.harvard.edu.
authors.forename: Panagiotis A
authors.initials: PA
authors.lastname: Konstantinopoulos
authors.affiliation: Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Raphael
authors.initials: R
authors.lastname: Ceccaldi
authors.affiliation: Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Early Drug Development Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.affiliation: Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. alan_dandrea@dfci.harvard.edu panagiotis_konstantinopoulos@dfci.harvard.edu.
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015415:Biomarkers; D000077216:Carcinoma, Ovarian Epithelial; D002986:Clinical Trials as Topic; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D014644:Genetic Variation; D059765:Homologous Recombination; D006801:Humans; D058990:Molecular Targeted Therapy; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers