The elephant and the blind men: Making sense of PARP inhibitors in homologous recombination deficient tumor cells

Frontiers in Oncology

Volumn 3 SEP, Issue , 2013, Pages

  De Lorenzo, Silvana B ^a   Patel, Anand G ^a,b   Hurley, Rachel M ^b   Kaufmann, Scott H ^a,b  

^a MAYO CLINIC   (United States)

^b MAYO GRADUATE SCHOOL   (United States)

Author keywords

BRCA1; BRCA2; Breast cancer; Homologous recombination; Non homologous end joining; Ovarian cancer; PARP inhibitor; Synthetic lethality

Indexed keywords

ATM PROTEIN; ATR PROTEIN; BLOOM SYNDROME HELICASE; BRCA1 ASSOCIATED RING DOMAIN PROTEIN 1; BRCA1 PROTEIN; BRCA2 PROTEIN; CAMPTOTHECIN; CHECKPOINT KINASE 1; CHECKPOINT KINASE 2; DNA; DNA DEPENDENT PROTEIN KINASE; EXONUCLEASE; FANCONI ANEMIA PROTEIN; HISTONE H2AX; KU ANTIGEN; MRE11 PROTEIN; NIBRIN; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE 1; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE 2; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE INHIBITOR; POLYDEOXYRIBONUCLEOTIDE SYNTHASE; RAD50 PROTEIN; RAD51 PROTEIN; RAD54 PROTEIN; TEMOZOLOMIDE; TOPOTECAN; UNINDEXED DRUG; VELIPARIB; XRCC1 PROTEIN; XRCC4 PROTEIN;

BREAST CANCER; CANCER INHIBITION; CELL CYCLE PHASE; CELL DEATH; CYTOTOXICITY; DNA DAMAGE; DNA END JOINING REPAIR; DNA REPLICATION; ELEPHANT; ENZYME INHIBITION; EXCISION REPAIR; GENE MUTATION; HOMOLOGOUS RECOMBINATION; HUMAN; LETHALITY; NEOPLASM; NONHUMAN; OVARY CANCER; PROTEIN EXPRESSION; REVIEW; TUMOR CELL;

EID: 84889575620     PISSN: None     EISSN: 2234943X     Source Type: Journal    
DOI: 10.3389/fonc.2013.00228     Document Type: Review

References (154)

1. Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG. PARP inhibition: PARP1 and beyond. Nat Rev Cancer (2010) 10(4):293-301. doi:10.1038/nrc2812
2. Telli ML, Ford JM. PARP inhibitors in breast cancer. Clin Adv Hematol Oncol (2010) 8(9):629-35.
3. Calvert H, Azzariti A. The clinical development of inhibitors of poly(ADP-ribose) polymerase. Ann Oncol (2011) 22(Suppl 1):i53-9. doi:10.1093/annonc/mdq667
4. Chionh F, Mitchell G, Lindeman GJ, Friedlander M, Scott CL. The role of poly adenosine diphosphate ribose polymerase inhibitors in breast and ovarian cancer: current status and future directions. Asia Pac J Clin Oncol (2011) 7(3):197-211. doi:10.1111/j.1743-7563.2011.01430.x
5. Plummer R. Poly(ADP-ribose) polymerase inhibition: a new direction for BRCA and triple-negative breast cancer? Breast Cancer Res (2011) 13(4):218. doi:10.1186/bcr2877
6. Irshad S, Ashworth A, Tutt A. Therapeutic potential of PARP inhibitors for metastatic breast cancer. Expert Rev Anticancer Ther (2011) 11(8):1243-51. doi:10.1586/era.11.52
7. Rios J, Puhalla S. PARP inhibitors in breast cancer: BRCA and beyond. Oncology (Williston Park) (2011) 25(11):1014-25.
8. Kummar S, Chen A, Parchment RE, Kinders RJ, Ji J, Tomaszewski JE, et al. Advances in using PARP inhibitors to treat cancer. BMC Med (2012) 10:25. doi:10.1186/1741-7015-10-25
9. Park SR, Chen A. Poly(adenosine diphosphate-ribose) polymerase inhibitors in cancer treatment. Hematol Oncol Clin North Am (2012) 26(3):649-70. doi:10.1016/j.hoc.2012.02.012
10. Tinker AV, Gelmon K. The role of PARP inhibitors in the treatment of ovarian carcinomas. Curr Pharm Des (2012) 18(25):3770-4. doi:10.2174/138161212802002823
11. Banerjee S, Kaye SB. New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential. Clin Cancer Res (2013) 19(5):961-8. doi:10.1158/1078-0432.CCR-12-2243
12. Curtin NJ, Szabo C. Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. Mol Aspects Med (2013). doi:10.1016/j.mam.2013.01.006
13. Hilton JF, Hadfield MJ, Tran MT, Shapiro GI. Poly(ADP-ribose) polymerase inhibitors as cancer therapy. Front Biosci (2013) 18:1392-406. doi:10.2741/4188
14. Durkacz BW, Omidiji O, Gray DA, Shall S. (ADP-ribose)n participates in DNA excision repair. Nature (1980) 283:593-6. doi:10.1038/283593a0
15. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature (2005) 434(7035):917-21. doi:10.1038/nature03445
16. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature (2005) 434(7035):913-7. doi:10.1038/nature03443
17. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med (2009) 361(2):123-34. doi:10.1056/NEJMoa0900212
18. Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol (2010) 28(15):2512-9. doi:10.1200/JCO.2009.26.9589
19. Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet (2010) 376(9737):245-51. doi:10.1016/S0140-6736(10)60893-8
20. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet (2010) 376(9737):235-44. doi:10.1016/S0140-6736(10)60892-6
21. Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol (2011) 12(9):852-61. doi:10.1016/S1470-2045(11)70214-5
22. Chan SL, Mok T. PARP inhibition in BRCA-mutated breast and ovarian cancers. Lancet (2010) 376(9737):211-3. doi:10.1016/S0140-6736(10)61119-1
23. Balmana J, Domchek SM, Tutt A, Garber JE. Stumbling blocks on the path to personalized medicine in breast cancer: the case of PARP inhibitors for BRCA1/2-associated cancers. Cancer Discov (2011) 1(1):29-34. doi:10.1158/2159-8274.CD-11-0048
24. Schreiber V, Dantzer F, Ame JC, de Murcia G. Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol (2006) 7(7):517-28. doi:10.1038/nrm1963
25. Hassa PO, Hottiger MO. The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases. Front Biosci (2008) 13:3046-82. doi:10.2741/2909
26. Quenet D, El Ramy R, Schreiber V, Dantzer F. The role of poly(ADP-ribosyl)ation in epigenetic events. Int J Biochem Cell Biol (2009) 41(1):60-5. doi:10.1016/j.biocel.2008.07.023
27. Caiafa P, Guastafierro T, Zampieri M. Epigenetics: poly(ADP-ribosyl)ation of PARP-1 regulates genomic methylation patterns. FASEB J (2009) 23(3):672-8. doi:10.1096/fj.08-123265
28. Krishnakumar R, Kraus WL. The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol Cell (2010) 39(1):8-24. doi:10.1016/j.molcel.2010.06.017
29. Messner S, Hottiger MO. Histone ADP-ribosylation in DNA repair, replication and transcription. Trends Cell Biol (2011) 21(9):534-42. doi:10.1016/j.tcb.2011.06.001
30. Luo X, Kraus WL. On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Dev (2012) 26(5):417-32. doi:10.1101/gad.183509.111
31. Sousa FG, Matuo R, Soares DG, Escargueil AE, Henriques JA, Larsen AK, et al. PARPs and the DNA damage response. Carcinogenesis (2012) 33(8):1433-40. doi:10.1093/carcin/bgs132
32. Gibson BA, Kraus WL. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol (2012) 13(7):411-24. doi:10.1038/nrm3376
33. Bai P, Canto C. The role of PARP-1 and PARP-2 enzymes in metabolic regulation and disease. Cell Metab (2012) 16(3):290-5.
34. Chambon P, Weill JD, Mandel P. Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem Biophys Res Commun (1963) 11:39-43. doi:10.1016/0006-291X(63)90024-X
35. Sugimura T, Fujimura S, Hasegawa S, Kawamura Y. Polymerization of the adenosine 5'-diphosphate ribose moiety of NAD by rat liver nuclear enzyme. Biochim Biophys Acta (1967) 138(2):438-41. doi:10.1016/0005-2787(67)90507-2
36. Nishizuka Y, Ueda K, Nakazawa K, Hayaishi O. Studies on the polymer of adenosine diphosphate ribose. I. Enzymic formation from nicotinamide adenine dinuclotide in mammalian nuclei. J Biol Chem (1967) 242(13):3164-71.
37. Ame JC, Spenlehauer C, de Murcia G. The PARP superfamily. Bioessays (2004) 26(8):882-93. doi:10.1002/bies.20085
38. Hassa PO, Haenni SS, Elser M, Hottiger MO. Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going? Microbiol Mol Biol Rev (2006) 70(3):789-829. doi:10.1128/MMBR.00040-05
39. Burkle A. Physiology and pathophysiology of poly(ADP-ribosyl)ation. Bioessays (2001) 23(9):795-806. doi:10.1002/bies.1115
40. Kim MY, Zhang T, Kraus WL. Poly(ADP-ribosyl)ation by PARP-1: 'PAR-laying' NAD+ into a nuclear signal. Genes Dev (2005) 19(17):1951-67.
41. Hassler M, Ladurner AG. Towards a structural understanding of PARP1 activation and related signalling ADP-ribosyl-transferases. Curr Opin Struct Biol (2012) 22(6):721-9. doi:10.1016/j.sbi.2012.08.005
42. Hong SJ, Dawson TM, Dawson VL. Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol Sci (2004) 25(5):259-64. doi:10.1016/j.tips.2004.03.005
43. Wahlberg E, Karlberg T, Kouznetsova E, Markova N, MacChiarulo A, Thorsell AG, et al. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat Biotechnol (2012) 30(3):283-8. doi:10.1038/nbt.2121
44. de Murcia G, Huletsky A, Poirier GG. Modulation of chromatin structure by poly(ADP-ribosyl)ation. Biochem Cell Biol (1988) 66(6):626-35. doi:10.1139/o88-072
45. Mendoza-Alvarez H, Alvarez-Gonzalez R. The 40 kDa carboxy-terminal domain of poly(ADP-ribose) polymerase-1 forms catalytically competent homo-and heterodimers in the absence of DNA. J Mol Biol (2004) 336(1):105-14. doi:10.1016/j.jmb.2003.11.055
46. Mendoza-Alvarez H, Alvarez-Gonzalez R. Poly(ADP-ribose) polymerase is a catalytic dimer and the automodification reaction is intermolecular. J Biol Chem (1993) 268(30):22575-80.
47. Langelier MF, Planck JL, Roy S, Pascal JM. Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1. Science (2012) 336(6082):728-32. doi:10.1126/science.1216338
48. Langelier MF, Pascal JM. PARP-1 mechanism for coupling DNA damage detection to poly(ADP-ribose) synthesis. Curr Opin Struct Biol (2013) 23(1):134-43. doi:10.1016/j.sbi.2013.01.003
49. Althaus FR, Richter C. ADP-ribosylation of proteins. Enzymology and biological significance. Mol Biol Biochem Biophys (1987) 37:1-126.
50. Realini CA, Althaus FR. Histone shuttling by poly(ADP-ribosylation). J Biol Chem (1992) 267(26):18858-65.
51. Satoh MS, Lindahl T. Role of poly (ADP-ribose) formation in DNA repair. Nature (1992) 356:356-8. doi:10.1038/356356a0
52. Malanga M, Althaus FR. Poly(ADP-ribose) reactivates stalled DNA topoisomerase I and induces DNA strand break resealing. J Biol Chem (2004) 279:5244-8. doi:10.1074/jbc.C300437200
53. Ahel I, Ahel D, Matsusaka T, Clark AJ, Pines J, Boulton SJ, et al. Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins. Nature (2008) 451(7174):81-5. doi:10.1038/nature06420
54. Gagné J-P, Isabelle M, Lo KS, Bourassa S, Hendzel MJ, Dawson VL, et al. Proteome-wide identification of poly(ADP-ribose) binding proteins and poly(ADP-ribose)-associated protein complexes. Nucleic Acids Res (2008) 36(22):6959-76. doi:10.1093/nar/gkn771
55. Gagne JP, Pic E, Isabelle M, Krietsch J, Ethier C, Paquet E, et al. Quantitative proteomics profiling of the poly(ADP-ribose)-related response to genotoxic stress. Nucleic Acids Res (2012) 40(16):7788-805. doi:10.1093/nar/gks486
56. de Murcia JM, Niedergang C, Trucco C, Ricoul M, Dutrillaux B, Mark M, et al. Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci U S A (1997) 94(14):7303-7. doi:10.1073/pnas.94.14.7303
57. Masson M, Niedergang C, Schreiber V, Muller S, Menissier-de Murcia J, de Murcia G. XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol Cell Biol (1998) 18(6):3563-71.
58. Trucco C, Oliver FJ, de Murcia G, Menissier-de Murcia J. DNA repair defect in poly(ADP-ribose) polymerase-deficient cell lines. Nucleic Acids Res (1998) 26(11):2644-9. doi:10.1093/nar/26.11.2644
59. Horton JK, Watson M, Stefanick DF, Shaughnessy DT, Taylor JA, Wilson SH. XRCC1 and DNA polymerase beta in cellular protection against cytotoxic DNA single-strand breaks. Cell Res (2008) 18(1):48-63. doi:10.1038/cr.2008.7
60. Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer (2012) 12(12):801-17. doi:10.1038/nrc3399
61. Okano S, Kanno S, Nakajima S, Yasui A. Cellular responses and repair of single-strand breaks introduced by UV damage endonuclease in mammalian cells. J Biol Chem (2000) 275(42):32635-41. doi:10.1074/jbc.M004085200
62. Izumi T, Wiederhold LR, Roy G, Roy R, Jaiswal A, Bhakat KK, et al. Mammalian DNA base excision repair proteins: their interactions and role in repair of oxidative DNA damage. Toxicology (2003) 193(1-2):43-65. doi:10.1016/S0300-483X(03)00289-0
63. Schultz N, Lopez E, Saleh-Gohari N, Helleday T. Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. Nucleic Acids Res (2003) 31(17):4959-64. doi:10.1093/nar/gkg703
64. Helleday T, Bryant HE, Schultz N. Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy. Cell Cycle (2005) 4(9):1176-8. doi:10.4161/cc.4.9.2031
65. Haince JF, Kozlov S, Dawson VL, Dawson TM, Hendzel MJ, Lavin MF, et al. Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. J Biol Chem (2007) 282(22):16441-53. doi:10.1074/jbc.M608406200
66. Haince JF, McDonald D, Rodrigue A, Dery U, Masson JY, Hendzel MJ, et al. PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. J Biol Chem (2008) 283(2):1197-208. doi:10.1074/jbc.M706734200
67. Wang M, Wu W, Wu W, Rosidi B, Zhang L, Wang H, et al. PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res (2006) 34(21):6170-82. doi:10.1093/nar/gkl840
68. Yang YG, Cortes U, Patnaik S, Jasin M, Wang ZQ. Ablation of PARP-1 does not interfere with the repair of DNA double-strand breaks, but compromises the reactivation of stalled replication forks. Oncogene (2004) 23(21):3872-82. doi:10.1038/sj.onc.1207491
69. Haince JF, Rouleau M, Hendzel MJ, Masson JY, Poirier GG. Targeting poly(ADP-ribosyl)ation: a promising approach in cancer therapy. Trends Mol Med (2005) 11(10):456-63. doi:10.1016/j.molmed.2005.08.003
70. Bryant HE, Petermann E, Schultz N, Jemth A-S, Loseva O, Issaeva N, et al. PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination. EMBO J (2009) 28(17):2601-15. doi:10.1038/emboj.2009.206
71. Ying S, Hamdy FC, Helleday T. Mre11-dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1. Cancer Res (2012) 72(11):2814-21. doi:10.1158/0008-5472.CAN-11-3417
72. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell (2010) 40(2):179-204. doi:10.1016/j.molcel.2010.09.019
73. Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer (2012) 12(1):68-78. doi:10.1038/nrc3181
74. Stracker TH, Petrini JH. The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol (2011) 12(2):90-103. doi:10.1038/nrm3047
75. Sartori AA, Lukas C, Coates J, Mistrik M, Fu S, Bartek J, et al. Human CtIP promotes DNA end resection. Nature (2007) 450(7169):509-14. doi:10.1038/nature06337
76. Chen L, Nievera CJ, Lee AY, Wu X. Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair. J Biol Chem (2008) 283(12):7713-20. doi:10.1074/jbc.M710245200
77. Paull TT. Making the best of the loose ends: Mre11/Rad50 complexes and Sae2 promote DNA double-strand break resection. DNA Repair (2010) 9(12):1283-91. doi:10.1016/j.dnarep.2010.09.015
78. Brosh RM Jr. DNA helicases involved in DNA repair and their roles in cancer. Nat Rev Cancer (2013) 13(8):542-58. doi:10.1038/nrc3560
79. Huertas P. DNA resection in eukaryotes: deciding how to fix the break. Nat Struct Mol Biol (2010) 17(1):11-6. doi:10.1038/nsmb.1710
80. Mimitou EP, Symington LS. DNA end resection-unraveling the tail. DNA Repair (2011) 10(3):344-8. doi:10.1016/j.dnarep.2010.12.004
81. Holloman WK. Unraveling the mechanism of BRCA2 in homologous recombination. Nat Struct Mol Biol (2011) 18(7):748-54.
82. Polo SE, Jackson SP. Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev (2011) 25(5):409-33. doi:10.1101/gad.2021311
83. Carreira A, Hilario J, Amitani I, Baskin RJ, Shivji MK, Venkitaraman AR, et al. The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51. Cell (2009) 136(6):1032-43. doi:10.1016/j.cell.2009.02.019
84. Trovesi C, Manfrini N, Falcettoni M, Longhese MP. Regulation of the DNA damage response by cyclin-dependent kinases. J Mol Biol (2013). doi:10.1016/j.jmb.2013.04.013
85. Peterson SE, Li Y, Wu-Baer F, Chait BT, Baer R, Yan H, et al. Activation of DSB processing requires phosphorylation of CtIP by ATR. Mol Cell (2013) 49(4):657-67. doi:10.1016/j.molcel.2012.11.020
86. Wang H, Shi LZ, Wong CC, Han X, Hwang PY, Truong LN, et al. The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-mediated double-strand break repair. PLoS Genet (2013) 9(2):e1003277. doi:10.1371/journal.pgen.1003277
87. Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A (2011) 108(44):18032-7. doi:10.1073/pnas.1115052108
88. Pennington KP, Swisher EM. Hereditary ovarian cancer: beyond the usual suspects. Gynecol Oncol (2012) 124(2):347-53. doi:10.1016/j.ygyno.2011.12.415
89. Berns EM, Bowtell DD. The changing view of high-grade serous ovarian cancer. Cancer Res (2012) 72(11):2701-4. doi:10.1158/0008-5472.CAN-11-3911
90. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature (2011) 474(7353):609-15. doi:10.1038/nature10166
91. Turner N, Tutt A, Ashworth A. Hallmarks of "BRCAness" in sporadic cancers. Nat Rev Cancer (2004) 4:814-9. doi:10.1038/nrc1457
92. Metzger-Filho O, Tutt A, de Azambuja E, Saini KS, Viale G, Loi S, et al. Dissecting the heterogeneity of triple-negative breast cancer. J Clin Oncol (2012) 30(15):1879-87. doi:10.1200/JCO.2011.38.2010
93. Crown J, O'Shaughnessy J, Gullo G. Emerging targeted therapies in triple-negative breast cancer. Ann Oncol (2012) 23(Suppl 6):vi56-65. doi:10.1093/annonc/mds196
94. Merritt MA, Cramer DW. Molecular pathogenesis of endometrial and ovarian cancer. Cancer Biomark (2010) 9(1-6):287-305. doi:10.3233/CBM-2011-0167
95. Hollander MC, Blumenthal GM, Dennis PA. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer (2011) 11(4):289-301. doi:10.1038/nrc3037
96. McCubrey JA, Steelman LS, Kempf CR, Chappell WH, Abrams SL, Stivala F, et al. Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways. J Cell Physiol (2011) 226(11):2762-81. doi:10.1002/jcp.22647
97. Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol (2012) 13(5):283-96. doi:10.1038/nrm3330
98. McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res (2006) 66(16):8109-15. doi:10.1158/0008-5472.CAN-06-0140
99. Williamson CT, Muzik H, Turhan AG, Zamo A, O'Connor MJ, Bebb DG, et al. ATM deficiency sensitizes mantle cell lymphoma cells to poly(ADP-ribose) polymerase-1 inhibitors. Mol Cancer Ther (2010) 9(2):347-57. doi:10.1158/1535-7163.MCT-09-0872
100. Weston VJ, Oldreive CE, Skowronska A, Oscier DG, Pratt G, Dyer MJ, et al. The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood (2010) 116(22):4578-87. doi:10.1182/blood-2010-01-265769
101. Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell (2007) 128(1):157-70. doi:10.1016/j.cell.2006.11.042
102. Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med (2009) 1(6-7):315-22. doi:10.1002/emmm.200900041
103. Nowsheen S, Cooper T, Stanley JA, Yang ES. Synthetic lethal interactions between EGFR and PARP inhibition in human triple negative breast cancer cells. PLoS One (2012) 7(10):e46614. doi:10.1371/journal.pone.0046614
104. Johnson N, Li YC, Walton ZE, Cheng KA, Li D, Rodig SJ, et al. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nat Med (2011) 17(7):875-82. doi:10.1038/nm.2377
105. Juvekar A, Burga LN, Hu H, Lunsford EP, Ibrahim YH, Balmana J, et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov (2012) 2(11):1048-63. doi:10.1158/2159-8290.CD-11-0336
106. Ibrahim YH, Garcia-Garcia C, Serra V, He L, Torres-Lockhart K, Prat A, et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov (2012) 2(11):1036-47. doi:10.1158/2159-8290.CD-11-0348
107. Huntoon CJ, Flatten KS, Wahner Hendrickson AE, Huehls AM, Sutor SL, Kaufmann SH, et al. ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status. Cancer Res (2013) 73(12):3683-91. doi:10.1158/0008-5472.CAN-13-0110
108. Hegan DC, Lu Y, Stachelek GC, Crosby ME, Bindra RS, Glazer PM. Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci U S A (2010) 107(5):2201-6. doi:10.1073/pnas.0904783107
109. Dobbs TA, Tainer JA, Lees-Miller SP. A structural model for regulation of NHEJ by DNA-PKcs autophosphorylation. DNA Repair (2010) 9(12):1307-14. doi:10.1016/j.dnarep.2010.09.019
110. Lieber MR. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem (2010) 79:181-211. doi:10.1146/annurev.biochem.052308.093131
111. Weterings E, Chen DJ. The endless tale of non-homologous end-joining. Cell Res (2008) 18(1):114-24. doi:10.1038/cr.2008.3
112. Zimmermann M, Lottersberger F, Buonomo SB, Sfeir A, de Lange T. 53BP1 regulates DSB repair using Rif1 to control 5' end resection. Science (2013) 339(6120):700-4. doi:10.1126/science.1231573
113. Di Virgilio M, Callen E, Yamane A, Zhang W, Jankovic M, Gitlin AD, et al. Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science (2013) 339(6120):711-5. doi:10.1126/science.1230624
114. Chapman JR, Barral P, Vannier JB, Borel V, Steger M, Tomas-Loba A, et al. RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol Cell (2013) 49(5):858-71. doi:10.1016/j.molcel.2013.01.002
115. Escribano-Diaz C, Orthwein A, Fradet-Turcotte A, Xing M, Young JT, Tkac J, et al. A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol Cell (2013) 49(5):872-83. doi:10.1016/j.molcel.2013.01.001
116. Patel A, Sarkaria J, Kaufmann SH. Nonhomologous end-joining drives PARP inhibitor synthetic lethality in homologous recombination-deficient cells. Proc Natl Acad Sci U S A (2011) 108:3406-11. doi:10.1073/pnas.1013715108
117. Symington LS, Gautier J. Double-strand break end resection and repair pathway choice. Annu Rev Genet (2011) 45:247-71. doi:10.1146/annurev-genet-110410-132435
118. Chapman JR, Taylor MR, Boulton SJ. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell (2012) 47(4):497-510. doi:10.1016/j.molcel.2012.07.029
119. Langerak P, Mejia-Ramirez E, Limbo O, Russell P. Release of Ku and MRN from DNA ends by Mre11 nuclease activity and Ctp1 is required for homologous recombination repair of double-strand breaks. PLoS Genet (2011) 7(9):e1002271. doi:10.1371/journal.pgen.1002271
120. Sun J, Lee KJ, Davis AJ, Chen DJ. Human Ku70/80 protein blocks exonuclease 1-mediated DNA resection in the presence of human Mre11 or Mre11/Rad50 protein complex. J Biol Chem (2012) 287(7):4936-45. doi:10.1074/jbc.M111.306167
121. Karanam K, Kafri R, Loewer A, Lahav G. Quantitative live cell imaging reveals a gradual shift between DNA repair mechanisms and a maximal use of HR in mid S phase. Mol Cell (2012) 47(2):320-9. doi:10.1016/j.molcel.2012.05.052
122. Dantzer F, Schreiber V, Niedergang C, Trucco C, Flatter E, De La Rubia G, et al. Involvement of poly(ADP-ribose) polymerase in base excision repair. Biochimie (1999) 81(1-2):69-75. doi:10.1016/S0300-9084(99)80040-6
123. De Vos M, Schreiber V, Dantzer F. The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art. Biochem Pharmacol (2012) 84(2):137-46. doi:10.1016/j.bcp.2012.03.018
124. Iglehart JD, Silver DP. Synthetic lethality-a new direction in cancer-drug development. N Engl J Med (2009) 361(2):189-91. doi:10.1056/NEJMe0903044
125. Yap TA, Sandhu SK, Carden CP, de Bono JS. Poly(ADP-ribose) polymerase (PARP) inhibitors: exploiting a synthetic lethal strategy in the clinic. CA Cancer J Clin (2011) 61(1):31-49. doi:10.3322/caac.20095
126. de Murcia G, Menissier de Murcia J. Poly(ADP-ribose) polymerase: a molecular nick-sensor. Trends Biochem Sci (1994) 19(4):172-6.
127. Juarez-Salinas H, Sims JL, Jacobson MK. Poly(ADP-ribose) levels in carcinogen-treated cells. Nature (1979) 282:740-1. doi:10.1038/282740a0
128. Benjamin RC, Gill DM. ADP-ribosylation in mammalian cell ghosts. Dependence of poly(ADP-ribose) synthesis on strand breakage in DNA. J Biol Chem (1980) 255(21):10493-501.
129. D'Amours D, Desnoyers S, D'Silva I, Poirier GG. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J (1999) 342(Pt 2):249-68. doi:10.1042/0264-6021:3420249
130. Kupper JH, deMurcia G, Bürkle A. Inhibition of Poly(ADP-ribosyl)ation by overexpressing the poly(ADP-ribose) polymerase DNA-binding domain in mammalian cells. J Biol Chem (1990) 265:18721-4.
131. Molinete M, Vermeulen W, Burkle A, Menissier-de Murcia J, Kupper JH, Hoeijmakers JH, et al. Overproduction of the poly(ADP-Ribose) polymerase DNA-binding domain blocks alkylation-induced DNA repair synthesis in mammalian cells. EMBO J (1993) 12:2109-17.
132. Patel AG, Flatten KS, Schneider PA, Dai NT, McDonald JS, Poirier GG, et al. Enhanced killing of cancer cells by poly(ADP-ribose) polymerase inhibitors and topoisomerase inhibitors reflects poisoning of both enzymes. J Biol Chem (2012) 287:4198-210. doi:10.1074/jbc.M111.296475
133. Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res (2012) 72(21):5588-99. doi:10.1158/0008-5472.CAN-12-2753
134. Li M, Yu X. Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. Cancer Cell (2013) 23(5):693-704. doi:10.1016/j.ccr.2013.03.025
135. Miwa M, Masutani M. PolyADP-ribosylation and cancer. Cancer Sci (2007) 98(10):1528-35. doi:10.1111/j.1349-7006.2007.00567.x
136. Li B, Navarro S, Kasahara N, Comai L. Identification and biochemical characterization of a Werner's syndrome protein complex with Ku70/80 and poly(ADP-ribose) polymerase-1. J Biol Chem (2004) 279(14):13659-67. doi:10.1074/jbc.M311606200
137. Hochegger H, Dejsuphong D, Fukushima T, Morrison C, Sonoda E, Schreiber V, et al. Parp-1 protects homologous recombination from interference by Ku and Ligase IV in vertebrate cells. EMBO J (2006) 25(6):1305-14. doi:10.1038/sj.emboj.7601015
138. Paddock MN, Bauman AT, Higdon R, Kolker E, Takeda S, Scharenberg AM. Competition between PARP-1 and Ku70 control the decision between high-fidelity and mutagenic DNA repair. DNA Repair (2011) 10(3):338-43. doi:10.1016/j.dnarep.2010.12.005
139. Murai J, Yang K, Dejsuphong D, Hirota K, Takeda S, D'Andrea AD. The USP1/UAF1 complex promotes double-strand break repair through homologous recombination. Mol Cell Biol (2011) 31(12):2462-9. doi:10.1128/MCB.05058-11
140. Williamson CT, Kubota E, Hamill JD, Klimowicz A, Ye R, Muzik H, et al. Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53. EMBO Mol Med (2012) 4(6):515-27. doi:10.1002/emmm.201200229
141. Bunting SF, Callen E, Wong N, Chen HT, Polato F, Gunn A, et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell (2010) 141(2):243-54. doi:10.1016/j.cell.2010.03.012
142. Cao L, Xu X, Bunting SF, Liu J, Wang RH, Cao LL, et al. A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Mol Cell (2009) 35(4):534-41. doi:10.1016/j.molcel.2009.06.037
143. Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, van der Gulden H, et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol (2010) 17(6):688-95. doi:10.1038/nsmb.1831
144. Liu LF. DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem (1989) 58:351-75. doi:10.1146/annurev.bi.58.070189.002031
145. Eng WK, Faucette L, Johnson RK, Sternglanz R. Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol Pharmacol (1988) 34(6):755-60.
146. Eng WK, McCabe FL, Tan KB, Mattern MR, Hofmann GA, Woessner RD, et al. Development of a stable camptothecin-resistant subline of P388 leukemia with reduced topoisomerase I content. Mol Pharmacol (1990) 38(4):471-80.
147. Liu X, Han EK, Anderson M, Shi Y, Semizarov D, Wang G, et al. Acquired resistance to combination treatment with temozolomide and ABT-888 is mediated by both base excision repair and homologous recombination DNA repair pathways. Mol Cancer Res (2009) 7(10):1686-92. doi:10.1158/1541-7786.MCR-09-0299
148. Patel AG, De Lorenzo SB, Flatten KS, Poirier GG, Kaufmann SH. Failure of iniparib to inhibit poly(ADP-ribose) polymerase in vitro. Clin Cancer Res (2012) 18(6):1655-62. doi:10.1158/1078-0432.CCR-11-2890
149. Gottipati P, Vischioni B, Schultz N, Solomons J, Bryant HE, Djureinovic T, et al. Poly(ADP-ribose) polymerase is hyperactivated in homologous recombination-defective cells. Cancer Res (2010) 70(13):5389-98. doi:10.1158/0008-5472.CAN-09-4716
150. Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol (2011) 5(4):387-93. doi:10.1016/j.molonc.2011.07.001
151. Caldecott KW. XRCC1 and DNA strand break repair. DNA Repair (2003) 2(9):955-69. doi:10.1016/S1568-7864(03)00118-6
152. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med (2001) 344:1038-42. doi:10.1056/NEJM200104053441402
153. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med (2011) 364(26):2507-16. doi:10.1056/NEJMoa1103782
154. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med (2012) 366(8):707-14. doi:10.1056/NEJMoa1112302