Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 143 No. 3132 (2013)

Targeting DNA double-strand break signalling and repair: recent advances in cancer therapy

  • Daniela Hühn
  • Hella A Bolck
  • Alessandro A Sartori
Cite this as:
Swiss Med Wkly. 2013;143:w13837


  1. Bundesamt für Statistik – Todesfälle: Anzahl, Entwicklung und Ursachen.
  2. Krebsliga Schweiz – Krebs in der Schweiz: wichtige Zahlen (Stand: Juni 2012).
  3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.
  4. Barnes DE, Lindahl T. Repair and genetic consequences of endogenous DNA base damage in mammalian cells. Annu Rev Genet. 2004;38:445–76.
  5. Hoeijmakers JHJ. DNA damage, aging, and cancer. N Engl J Med. 2009;361(15):1475–85.
  6. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–8.
  7. Bouwman P, Jonkers J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587–98.
  8. Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012;481(7381):287–94.
  9. Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer. 2012;12(12):801–17.
  10. Falck J, Coates J, Jackson SP. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature. 2005;434(7033):605–11.
  11. Derheimer FA, Kastan MB. Multiple roles of ATM in monitoring and maintaining DNA integrity. FEBS Lett. 2010;584(17):3675–81.
  12. Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. 2006;7(5):335–46.
  13. Schärer OD. DNA interstrand crosslinks: natural and drug-induced DNA adducts that induce unique cellular responses. Chembiochem. 2005;6(1):27–32.
  14. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010;40(2):179–204.
  15. Chapman JR, Taylor MRG, Boulton SJ. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell. 2012;47(4):497–510.
  16. Symington LS, Gautier J. Double-strand break end resection and repair pathway choice. Annu Rev Genet. 2011;45:247–71.
  17. 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.
  18. Moynahan ME, Jasin M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol. 2010;11(3):196–207.
  19. Jackson SP. Sensing and repairing DNA double-strand breaks. Carcinogenesis. 2002;23(5):687–96.
  20. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.
  21. Ma CX, Cai S, Li S, Ryan CE, Guo Z, Schaiff WT, et al. Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models. J Clin Invest. 2012;122(4):1541–52.
  22. Gaudin D, Yielding KL. Response of a “resistant” plasmacytoma to alkylating agents and x-ray in combination with the ‘excision’ repair inhibitors caffeine and chloroquine. Proc Soc Exp Biol Med. 1969;131(4):1413–6.
  23. Sarkaria JN, Busby EC, Tibbetts RS, Roos P, Taya Y, Karnitz LM, et al. Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res. 1999;59(17):4375–82.
  24. Blasina A, Price BD, Turenne GA, McGowan CH. Caffeine inhibits the checkpoint kinase ATM. Curr Biol. 1999;9(19):1135–8.
  25. Hickson I, Zhao Y, Richardson CJ, Green SJ, Martin NMB, Orr AI, et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 2004;64(24):9152–9.
  26. Knight ZA. Small molecule inhibitors of the PI3-kinase family. Curr Top Microbiol Immunol. 2010;347:263–78.
  27. Golding SE, Rosenberg E, Valerie N, Hussaini I, Frigerio M, Cockcroft XF, et al. Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Mol Cancer Ther. 2009;8(10):2894–902.
  28. Wagner JM, Kaufmann SH. Prospects for the Use of ATR Inhibitors to Treat Cancer. Pharmaceuticals. 2010;3(5):1311–34.
  29. Peasland A, Wang L-Z, Rowling E, Kyle S, Chen T, Hopkins A, et al. Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines. Br J Cancer. 2011;105(3):372–81.
  30. Arris CE, Boyle FT, Calvert AH, Curtin NJ, Endicott JA, Garman EF, et al. Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J Med Chem. 2000;43(15):2797–804.
  31. Reaper PM, Griffiths MR, Long JM, Charrier J-D, MacCormick S, Charlton PA, et al. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol. 2011;7(7):428–30.
  32. Prevo R, Fokas E, Reaper PM, Charlton PA, Pollard JR, McKenna WG, et al. The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther. 2012;13(11):1072–81.
  33. Toledo LI, Murga M, Zur R, Soria R, Rodriguez A, Martinez S, et al. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol. 2011;18(6):721–7.
  34. Yang F, Qian X-J, Qin W, Deng R, Wu X-Q, Qin J, et al. Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 Has a Therapeutic Potential and Sensitizes Cisplatin in Nasopharyngeal Carcinoma. PLoS ONE. 2013;8(3):e59879.
  35. Mukherjee B, Tomimatsu N, Amancherla K, Camacho CV, Pichamoorthy N, Burma S. The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. Neoplasia. 2012;14(1):34–43.
  36. Takahashi I, Saitoh Y, Yoshida M, Sano H, Nakano H, Morimoto M, et al. UCN-01 and UCN-02, new selective inhibitors of protein kinase C. II. Purification, physico-chemical properties, structural determination and biological activities. J Antibiot. 1989;42(4):571–6.
  37. Graves PR, Yu L, Schwarz JK, Gales J, Sausville EA, O'Connor PM, et al. The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J Biol Chem. 2000;275(8):5600–5.
  38. Zhao B, Bower MJ, McDevitt PJ, Zhao H, Davis ST, Johanson KO, et al. Structural basis for Chk1 inhibition by UCN-01. J Biol Chem. 2002;277(48):46609–15.
  39. Guzi TJ, Paruch K, Dwyer MP, Labroli M, Shanahan F, Davis N, et al. Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. Mol Cancer Ther. 2011;10(4):591–602.
  40. De Witt Hamer PC, Mir SE, Noske D, Van Noorden CJF, Würdinger T. WEE1 kinase targeting combined with DNA-damaging cancer therapy catalyzes mitotic catastrophe. Clin Cancer Res. 2011;17(13):4200–7.
  41. Lavecchia A, Di Giovanni C, Novellino E. CDC25 phosphatase inhibitors: an update. Mini Rev Med Chem. 2012;12(1):62–73.
  42. Brezak M-C, Valette A, Quaranta M, Contour-Galcera M-O, Jullien D, Lavergne O, et al. IRC-083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cells. Int J Cancer. 2009;124(6):1449–56.
  43. Veuger SJ, Curtin NJ, Richardson CJ, Smith GCM, Durkacz BW. Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1. Cancer Res. 2003;63(18):6008–15.
  44. Leahy JJJ, Golding BT, Griffin RJ, Hardcastle IR, Richardson C, Rigoreau L, et al. Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries. Bioorg Med Chem Lett. 2004;14(24):6083–7.
  45. Munck JM, Batey MA, Zhao Y, Jenkins H, Richardson CJ, Cano C, et al. Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K. Mol Cancer Ther. 2012;11(8):1789–98.
  46. Dupré A, Boyer-Chatenet L, Sattler RM, Modi AP, Lee J-H, Nicolette ML, et al. A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex. Nat Chem Biol. 2008;4(2):119–25.
  47. 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.
  48. Neher TM, Bodenmiller D, Fitch RW, Jalal SI, Turchi JJ. Novel irreversible small molecule inhibitors of replication protein A display single-agent activity and synergize with cisplatin. Mol Cancer Ther. 2011;10(10):1796–806.
  49. Huang F, Motlekar NA, Burgwin CM, Napper AD, Diamond SL, Mazin AV. Identification of specific inhibitors of human RAD51 recombinase using high-throughput screening. ACS Chem Biol. 2011;6(6):628–35.
  50. Budke B, Logan HL, Kalin JH, Zelivianskaia AS, Cameron McGuire W, Miller LL, et al. RI-1: a chemical inhibitor of RAD51 that disrupts homologous recombination in human cells. Nucleic Acids Res. 2012;40(15):7347–57.
  51. Nomme J, Renodon-Cornière A, Asanomi Y, Sakaguchi K, Stasiak AZ, Stasiak A, et al. Design of potent inhibitors of human RAD51 recombinase based on BRC motifs of BRCA2 protein: modeling and experimental validation of a chimera peptide. J Med Chem. 2010;53(15):5782–91.
  52. Pessetto ZY, Yan Y, Bessho T, Natarajan A. Inhibition of BRCT(BRCA1)-phosphoprotein interaction enhances the cytotoxic effect of olaparib in breast cancer cells: a proof of concept study for synthetic lethal therapeutic option. Breast Cancer Res Treat. 2012;134(2):511–7.
  53. Farmer H, McCabe N, Lord CJ, Tutt ANJ, 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.
  54. 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.
  55. 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.
  56. 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.
  57. Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer. 2004;4(10):814–9.
  58. 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.
  59. Huehls AM, Wagner JM, Huntoon CJ, Karnitz LM. Identification of DNA repair pathways that affect the survival of ovarian cancer cells treated with a poly(ADP-ribose) polymerase inhibitor in a novel drug combination. Mol Pharmacol. 2012;82(4):767–76.
  60. 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.
  61. Park SR, Chen A. Poly(Adenosine diphosphate-ribose) polymerase inhibitors in cancer treatment. Hematol Oncol Clin North Am. 2012;26(3):649–70–ix.
  62. Murai J, Huang S-YN, 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.
  63. O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364(3):205–14.
  64. Guha M. PARP inhibitors stumble in breast cancer. Nat Biotechnol. 2011;29(5):373–4.
  65. Liu X, Shi Y, Maag DX, Palma JP, Patterson MJ, Ellis PA, et al. Iniparib nonselectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor. Clin Cancer Res. 2012;18(2):510–23.
  66. 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.
  67. 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.
  68. Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim J-S, et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2009;1(6-7):315–22.
  69. Dedes KJ, Wetterskog D, Mendes-Pereira AM, Natrajan R, Lambros MB, Geyer FC, et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010;2(53):53ra75.
  70. Konstantinopoulos PA, Spentzos D, Karlan BY, Taniguchi T, Fountzilas E, Francoeur N, et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol. 2010;28(22):3555–61.
  71. Tung N, Wang Y, Collins LC, Kaplan J, Li H, Gelman R, et al. Estrogen receptor positive breast cancers in BRCA1 mutation carriers: clinical risk factors and pathologic features. Breast Cancer Res. 2010;12(1):R12.
  72. Oplustilova L, Wolanin K, Mistrik M, Korinkova G, Simkova D, Bouchal J, et al. Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment. Cell Cycle. 2012;11(20):3837–50.
  73. Jaspers JE, Kersbergen A, Boon U, Sol W, van Deemter L, Zander SA, et al. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discov. 2013;3(1):68–81.
  74. Barber LJ, Sandhu S, Chen L, Campbell J, Kozarewa I, Fenwick K, et al. Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor. J Pathol. 2013;229(3):422–9.
  75. Poumpouridou N, Kroupis C. Hereditary breast cancer: beyond BRCA genetic analysis; PALB2 emerges. Clin Chem Lab Med. 2012;50(3):423–34.
  76. Sultana R, McNeill DR, Abbotts R, Mohammed MZ, Zdzienicka MZ, Qutob H, et al. Synthetic lethal targeting of DNA double-strand break repair deficient cells by human apurinic/apyrimidinic endonuclease inhibitors. Int J Cancer. 2012;131(10):2433–44.
  77. Ferrao PT, Bukczynska EP, Johnstone RW, McArthur GA. Efficacy of CHK inhibitors as single agents in MYC-driven lymphoma cells. Oncogene. 2012;31(13):1661–72.
  78. Ivashkevich A, Redon CE, Nakamura AJ, Martin RF, Martin OA. Use of the γ-H2AX assay to monitor DNA damage and repair in translational cancer research. Cancer Lett. 2012;327(1-2):123–33.
  79. Kennedy RD, Chen CC, Stuckert P, Archila EM, la Vega De MA, Moreau LA, et al. Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated. J Clin Invest. 2007;117(5):1440–9.
  80. Chen CC, Kennedy RD, Sidi S, Look AT, D’Andrea A. CHK1 inhibition as a strategy for targeting Fanconi Anemia (FA) DNA repair pathway deficient tumors. Mol Cancer. 2009;8:24.
  81. Bartek J, Lukas J, Bartkova J. DNA damage response as an anti-cancer barrier: damage threshold and the concept of 'conditional haploinsufficiency'. Cell Cycle. 2007;6(19):2344–7.
  82. Kerzendorfer C, O'Driscoll M. Human DNA damage response and repair deficiency syndromes: linking genomic instability and cell cycle checkpoint proficiency. DNA Repair (Amst.). 2009;8(9):1139–52.
  83. Chen P-L, Liu F, Cai S, Lin X, Li A, Chen Y, et al. Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency. Mol Cell Biol. 2005;25(9):3535–42.
  84. Brown EJ, Baltimore D. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 2000;14(4):397–402.
  85. Halazonetis TD, Gorgoulis VG, Bartek J. An oncogene-induced DNA damage model for cancer development. Science. 2008;319(5868):1352–5.
  86. Vollebergh MA, Jonkers J, Linn SC. Genomic instability in breast and ovarian cancers: translation into clinical predictive biomarkers. Cell Mol Life Sci. 2012;69(2):223–45.
  87. Martin SA, McCabe N, Mullarkey M, Cummins R, Burgess DJ, Nakabeppu Y, et al. DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1. Cancer Cell. 2010;17(3):235–48.
  88. Zhang X, Wan G, Berger FG, He X, Lu X. The ATM kinase induces microRNA biogenesis in the DNA damage response. Mol Cell. 2011;41(4):371–83.
  89. Wang Y, Huang J-W, Li M, Cavenee WK, Mitchell PS, Zhou X, et al. MicroRNA-138 modulates DNA damage response by repressing histone H2AX expression. Mol Cancer Res. 2011;9(8):1100–11.
  90. Landau D-A, Slack FJ. MicroRNAs in mutagenesis, genomic instability, and DNA repair. Semin Oncol. 2011;38(6):743–51.
  91. Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, et al. miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell. 2011;41(2):210–20.
  92. Chang S, Wang R-H, Akagi K, Kim K-A, Martin BK, Cavallone L, et al. Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155. Nat Med. 2011;17(10):1275–82.
  93. Jiang S, Zhang H-W, Lu M-H, He X-H, Li Y, Gu H, et al. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res. 2010;70(8):3119–27.
  94. Broderick JA, Zamore PD. MicroRNA therapeutics. Gene Ther. 2011;18(12):1104–10.
  95. Li Y, Yang D-Q. The ATM inhibitor KU-55933 suppresses cell proliferation and induces apoptosis by blocking Akt in cancer cells with overactivated Akt. Mol Cancer Ther. 2010;9(1):113–25.
  96. Charrier J-D, Durrant SJ, Golec JMC, Kay DP, Knegtel RMA, MacCormick S, et al. Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem. 2011;54(7):2320–30.
  97. Zhao Y, Thomas HD, Batey MA, Cowell IG, Richardson CJ, Griffin RJ, et al. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res. 2006;66(10):5354–62.
  98. Willmore E, de Caux S, Sunter NJ, Tilby MJ, Jackson GH, Austin CA, et al. A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia. Blood. 2004;103(12):4659–65.
  99. Tang Y, Hamed HA, Poklepovic A, Dai Y, Grant S, Dent P. Poly(ADP-ribose) polymerase 1 modulates the lethality of CHK1 inhibitors in mammary tumors. Mol Pharmacol. 2012;82(2):322–32.
  100. Huang F, Mazina OM, Zentner IJ, Cocklin S, Mazin AV. Inhibition of homologous recombination in human cells by targeting RAD51 recombinase. J Med Chem. 2012;55(7):3011–20.
  101. Samol J, Ranson M, Scott E, Macpherson E, Carmichael J, Thomas A, et al. Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Invest New Drugs. 2012;30(4):1493–500.
  102. Kummar S, Ji J, Morgan R, Lenz H-J, Puhalla SL, Belani CP, et al. A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin Cancer Res. 2012;18(6):1726–34.
  103. Kummar S, Chen A, Ji J, Zhang Y, Reid JM, Ames M, et al. Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res. 2011;71(17):5626–34.
  104. 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 I inhibitors reflects poisoning of both enzymes. J Biol Chem. 2012;287(6):4198–210.
  105. Plummer R, Lorigan P, Steven N, Scott L, Middleton MR, Wilson RH, et al. A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemother Pharmacol. 2013;71(5):1191–9.
  106. Sandhu SK, Wenham RM, Wilding G, McFadden M, Sun L, Toniatti C, et al. First-in-human trial of a poly (ADP-ribose) polymerase (PARP) inhibitor MK-4827 in advanced cancer patients (pts) with antitumor activity in BRCA-deficient and sporadic ovarian cancers. J Clin Oncol. (Meeting Abstracts). 2010;28(15_suppl):3001.
  107. Javle M, Curtin NJ. The role of PARP in DNA repair and its therapeutic exploitation. Br J Cancer. 2011;105(8):1114–22.