title: Synthetic lethality and cancer therapy: lessons learned from the development of PARP inhibitors.
abstract: The genetic concept of synthetic lethality, in which the combination or synthesis of mutations in multiple genes results in cell death, provides a framework to design novel therapeutic approaches to cancer. Already there are promising indications, from clinical trials exploiting this concept by using poly(ADP-ribose) polymerase (PARP) inhibitors in patients with germline BRCA1 or BRCA2 gene mutations, that this approach could be beneficial. We discuss the biological rationale for BRCA-PARP synthetic lethality, how the synthetic lethal approach is being assessed in the clinic, and how mechanisms of resistance are starting to be dissected. Applying the synthetic lethal concept to target non-BRCA-mutant cancers also has clear potential, and we discuss how some of the principles learned in developing PARP inhibitors might also drive the development of additional genetic approaches.
authors.affiliation: The Breakthrough Breast Cancer Research Center, The Institute of Cancer Research, London, United Kingdom and.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: Tutt
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D001549:Benzamides / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010793:Phthalazines / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C090712:iniparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C531550:olaparib
keywords: BRCA1; BRCA2; breast cancer; drug resistance; ovarian cancer