title: Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations.
abstract: Utilizing the concept of synthetic lethality has provided new opportunities for the development of targeted therapies, by allowing the targeting of loss of function genetic aberrations. In cancer cells with BRCA1 or BRCA2 loss of function, which harbor deficiency of DNA repair by homologous recombination, inhibition of PARP1 enzymatic activity leads to an accumulation of single strand breaks that are converted to double strand breaks but cannot be repaired by homologous recombination. Inhibition of PARP has therefore been advanced as a novel targeted therapy for cancers harboring BRCA1/2 mutations. Preclinical and preliminary clinical evidence, however, suggests a potentially broader scope for PARP inhibitors. Loss of function of various proteins involved in double strand break repair other than BRCA1/2 has been suggested to be synthetically lethal with PARP inhibition. Inactivation of these genes has been reported in a subset of human cancers and might therefore constitute predictive biomarkers for PARP inhibition. Here we discuss the evidence that the clinical use of PARP inhibition may be broader than targeting of cancers in BRCA1/2 germ-line mutation carriers.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Konstantin J
authors.initials: KJ
authors.lastname: Dedes
authors.forename: Paul M
authors.initials: PM
authors.lastname: Wilkerson
authors.forename: Daniel
authors.initials: D
authors.lastname: Wetterskog
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D024682:BRCA2 Protein / Q000172:deficiency* / Q000235:genetics; D002986:Clinical Trials as Topic; D019175:DNA Methylation / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004843:Epistasis, Genetic; D005260:Female; D015870:Gene Expression; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases