title: Targeting DNA Repair in Cancer: Beyond PARP Inhibitors.
abstract: Germline aberrations in critical DNA-repair and DNA damage-response (DDR) genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers. Herein, we detail how cellular DDR processes engage various proteins that sense DNA damage, initiate signaling pathways to promote cell-cycle checkpoint activation, trigger apoptosis, and coordinate DNA repair. We focus on novel therapeutic strategies targeting promising DDR targets and discuss challenges of patient selection and the development of rational drug combinations.
  
  
  
  Various inhibitors of DDR components are in preclinical and clinical development. A thorough understanding of DDR pathway complexities must now be combined with strategies and lessons learned from the successful registration of PARP inhibitors in order to fully exploit the potential of DDR inhibitors and to ensure their long-term clinical success. Cancer Discov; 7(1); 20-37. ©2016 AACR.
authors.affiliation: Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Brown
authors.affiliation: Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: Brent
authors.initials: B
authors.lastname: O'Carrigan
authors.affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.|The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
authors.affiliation: Royal Marsden NHS Foundation Trust, London, United Kingdom. timothy.yap@icr.ac.uk.|The Institute of Cancer Research, London, United Kingdom.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004260:DNA Repair / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors