title: Mechanisms of resistance to therapies targeting BRCA-mutant cancers.
abstract: Synthetic lethality provides a potential mechanistic framework for the therapeutic targeting of genetic and functional deficiencies in cancers and is now being explored widely. The first clinical exemplification of synthetic lethality in cancer has been the exploitation of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of cancers with defects in the BRCA1 or BRCA2 tumor suppressor proteins, which are involved in the repair of DNA damage. Although this approach has shown promise, multiple potential resistance mechanisms have been identified. In this Perspective, we discuss these mechanisms and their relevance to the development of selective therapies for BRCA-deficient cancers.
authors.affiliation: The Breakthrough Breast Cancer Research Centre and Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D000818:Animals; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017671:Platinum Compounds / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D058615:Synthetic Biology; D057170:Translational Research, Biomedical; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D017671:Platinum Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D011065:Poly(ADP-ribose) Polymerases