title: PARP inhibitors: Synthetic lethality in the clinic.
abstract: PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in eitherBRCA1orBRCA2are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.
authors.affiliation: The Cancer Research UK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. chris.lord@icr.ac.uk alan.ashworth@ucsf.edu.
authors.forename: Christopher J
authors.identifier: 0000-0002-3226-0515
authors.initials: CJ
authors.lastname: Lord
authors.affiliation: University of California, San Francisco (UCSF), Helen Diller Family Comprehensive Cancer Center, 1450 Third Street, San Francisco, CA 94158, USA. chris.lord@icr.ac.uk alan.ashworth@ucsf.edu.
authors.forename: Alan
authors.identifier: 0000-0003-1446-7878
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D024221:Antineoplastic Protocols; D024682:BRCA2 Protein / Q000235:genetics; D002986:Clinical Trials as Topic; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000072020:Synthetic Lethal Mutations; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases