title: Poly (ADP-ribose) polymerase as a novel therapeutic target in cancer.
abstract: Cancer chemotherapy exploits limitations in repairing DNA damage in order to kill proliferating malignant cells. Recent evidence suggests that cancers within and across tissue types have specific defects in DNA repair pathways, and that these defects may predispose for sensitivity and resistance to various classes of cytotoxic agents. Poly (ADP-ribose) polymerase (PARP) and BRCA proteins are central to the repair of DNA strand breaks and, when defective, lead to the accumulation of mutations introduced by error-prone DNA repair. Breast, ovarian, and other cancers develop in the setting of BRCA deficiency, and these cancers may be more sensitive to cytotoxic agents that induce DNA strand breaks, as well as inhibitors of PARP activity. A series of recent clinical trials has tested whether PARP inhibitors can achieve synthetic lethality in BRCA-pathway-deficient tumors. Future studies must seek to identify sporadic cancers that harbor genomic instability, rendering susceptibility to agents that induce additional and lethal DNA damage.
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Annunziata
authors.forename: Joyce
authors.initials: J
authors.lastname: O'Shaughnessy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D030342:Genetic Diseases, Inborn / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology*; D011995:Recombination, Genetic / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases
references.citation: FEBS J. 2009 Nov;276(21):6074-83
references.pmid: 19788416
references.citation: Ann N Y Acad Sci. 2009 Feb;1155:132-40
references.pmid: 19250200
references.citation: Mol Cell Biol. 2007 Oct;27(19):6733-41
references.pmid: 17664283
references.citation: Cell. 2007 Jan 12;128(1):157-70
references.pmid: 17218262
references.citation: J Clin Oncol. 2009 Mar 10;27(8):1160-7
references.pmid: 19204204
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1680-5
references.pmid: 18230721
references.citation: Curr Opin Pharmacol. 2008 Aug;8(4):363-9
references.pmid: 18644251
references.citation: Mol Cell Biol. 2005 Aug;25(16):7158-69
references.pmid: 16055725
references.citation: Cell Res. 2008 Jan;18(1):134-47
references.pmid: 18157161
references.citation: Nat Rev Cancer. 2010 Apr;10(4):293-301
references.pmid: 20200537
references.citation: J Steroid Biochem Mol Biol. 2006 Nov;101(4-5):204-15
references.pmid: 16982187
references.citation: Breast Cancer Res. 2009;11(4):R47
references.pmid: 19589159
references.citation: Cancer Res. 2008 Feb 15;68(4):998-1002
references.pmid: 18281473
references.citation: Mol Cancer Res. 2009 Aug;7(8):1304-9
references.pmid: 19671671
references.citation: Trends Mol Med. 2002 Dec;8(12):571-6
references.pmid: 12470990
references.citation: Nat Rev Cancer. 2003 Jan;3(1):23-34
references.pmid: 12509764
references.citation: Biochem Pharmacol. 1999 Apr 1;57(7):727-41
references.pmid: 10075079
references.citation: J Biol Chem. 2008 Dec 26;283(52):36132-9
references.pmid: 18978354
references.citation: J Clin Oncol. 2007 Apr 10;25(11):1329-33
references.pmid: 17416853
references.citation: Clin Cancer Res. 2009 Mar 15;15(6):2192-203
references.pmid: 19276285
references.citation: N Engl J Med. 2009 Jul 9;361(2):189-91
references.pmid: 19553640
references.citation: Nature. 2002 Jan 31;415(6871):530-6
references.pmid: 11823860
references.citation: Trends Mol Med. 2006 Sep;12(9):440-50
references.pmid: 16899408
references.citation: Breast Cancer Res Treat. 2008 Sep;111(1):113-20
references.pmid: 17932744
references.citation: Nature. 2005 Apr 14;434(7035):917-21
references.pmid: 15829967
references.citation: Semin Oncol. 2009 Apr;36(2 Suppl 1):S42-51
references.pmid: 19393835
references.citation: N Engl J Med. 2009 Jul 9;361(2):123-34
references.pmid: 19553641
references.citation: Cancer Epidemiol Biomarkers Prev. 2007 Oct;16(10):2024-32
references.pmid: 17932350
references.citation: Breast Cancer Res. 2008;10(6):R101
references.pmid: 19055754
references.citation: Nat Med. 2009 Aug;15(8):907-13
references.pmid: 19648928
references.citation: Nature. 2005 Apr 14;434(7035):913-7
references.pmid: 15829966
references.citation: Annu Rev Genomics Hum Genet. 2008;9:321-45
references.pmid: 18544032
references.citation: Cancer Res. 2009 Apr 15;69(8):3589-96
references.pmid: 19351835
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7155-60
references.pmid: 19369211
references.citation: N Engl J Med. 2009 Oct 8;361(15):1475-85
references.pmid: 19812404
references.citation: Mutat Res. 2008 Feb 1;638(1-2):110-21
references.pmid: 17961607
references.citation: J Clin Oncol. 2010 May 20;28(15):2512-9
references.pmid: 20406929
references.citation: Cancer Res. 2004 Aug 1;64(15):5051-3
references.pmid: 15289302
references.citation: Nat Rev Cancer. 2007 Nov;7(11):861-9
references.pmid: 17943134
references.citation: Nat Med. 2009 Aug;15(8):842-4
references.pmid: 19661985
references.citation: Breast Cancer Res Treat. 2009 May;115(2):359-63
references.pmid: 18649131
references.citation: Breast Cancer Res Treat. 2012 Apr;132(2):379-89
references.pmid: 20614180
references.citation: Mol Oncol. 2008 Dec;2(4):296-316
references.pmid: 19383352
references.citation: Nature. 2008 Feb 28;451(7182):1111-5
references.pmid: 18264088
references.citation: J Clin Oncol. 2010 Mar 1;28(7):1145-53
references.pmid: 20100965
references.citation: EMBO Mol Med. 2010 Apr;2(4):130-42
references.pmid: 20373286
references.citation: Nat Rev Cancer. 2005 Sep;5(9):689-98
references.pmid: 16110319
references.citation: Nat Genet. 2006 Sep;38(9):1043-8
references.pmid: 16921376
references.citation: Oncogene. 2008 Apr 10;27(17):2501-6
references.pmid: 17982490
references.citation: Science. 2006 Dec 1;314(5804):1467-70
references.pmid: 17138902
references.citation: Nature. 2008 Feb 28;451(7182):1116-20
references.pmid: 18264087
references.citation: Nat Rev Mol Cell Biol. 2008 Oct;9(10):759-69
references.pmid: 18813293
references.citation: EMBO Mol Med. 2009 Sep;1(6-7):315-22
references.pmid: 20049735
references.citation: Biochem Pharmacol. 2003 Jan 15;65(2):275-82
references.pmid: 12504803
references.citation: Breast Cancer Res Treat. 2009 Aug;116(3):479-89
references.pmid: 18704682
references.citation: Bioessays. 2008 Apr;30(4):291-5
references.pmid: 18348153
references.citation: Mol Cancer Res. 2009 Apr;7(4):511-22
references.pmid: 19372580
references.citation: DNA Repair (Amst). 2006 Sep 8;5(9-10):1199-212
references.pmid: 16822725
references.citation: IUBMB Life. 2005 Feb;57(2):73-81
references.pmid: 16036566
references.citation: Clin Cancer Res. 2007 Mar 1;13(5):1383-8
references.pmid: 17332279