title: Poly(ADP-ribose) polymerase activity and inhibition in cancer.
abstract: Genomic instability resultant from defective DNA repair mechanisms is a fundamental hallmark of cancer. The poly(ADP-ribose) polymerase (PARP) proteins 1, 2 and 3 catalyze the polymerization of poly(ADP-ribose) and covalent attachment to proteins in a phylogenetically ancient form of protein modification. PARPs play a role in base excision repair, homologous recombination, and non-homologous end joining. The discovery that loss of PARP activity had cytotoxic effects in cells deficient in homologous recombination has sparked a decade of translational research efforts that culminated in the FDA approval of an oral PARP inhibitor for clinical use in patients with ovarian cancer and defective homologous recombination. Five PARP inhibitors are now in late-stage development in clinical trials that are seeking to expand the understanding of targeted therapies and DNA repair defects in human cancer. This review examines the cell biology of PARP, the discovery of synthetic lethality with HR deficiency, the clinical development of PARP inhibitors, and the role of PARP inhibitors in ongoing clinical trials and clinical practice.
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, 1700 6th Avenue South, 176F Hazelrig-Salter Radiation Oncology Center, Room 2232-N, Birmingham, AL 35249-6832, United States.
authors.forename: Caleb
authors.initials: C
authors.lastname: Dulaney
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, 1700 6th Avenue South, 176F Hazelrig-Salter Radiation Oncology Center, Room 2232-N, Birmingham, AL 35249-6832, United States.
authors.forename: Samuel
authors.initials: S
authors.lastname: Marcrom
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, 1700 6th Avenue South, 176F Hazelrig-Salter Radiation Oncology Center, Room 2232-N, Birmingham, AL 35249-6832, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stanley
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, 1700 6th Avenue South, 176F Hazelrig-Salter Radiation Oncology Center, Room 2232-N, Birmingham, AL 35249-6832, United States. Electronic address: eyang@uab.edu.
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Yang
mesh_terms: D000818:Animals; D004260:DNA Repair / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases
keywords: DNA repair; PARP; PARP inhibitors; Poly(ADP-ribose) polymerase; Synthetic lethality