Targeting ATR for Cancer Therapy: Profile and Expectations for ATR Inhibitors

  • Nicola Curtin
  • John PollardEmail author
Part of the Cancer Drug Discovery and Development book series (CDD&D)


ATR is a highly versatile player in the DNA damage response (DDR) that signals DNA damage via CHK1 phosphorylation to the S and G2/M cell cycle checkpoints and to promote DNA repair. It is activated by ssDNA, principally occurring due to replication stress that is caused by unrepaired endogenous DNA damage or induced by a variety of anticancer chemotherapy and ionizing radiation. Since an almost ubiquitous feature of cancer cells is loss of G1 control, e.g., through p53 mutation, it is thought that their greater dependence on S and G2/M checkpoint function may render them more susceptible to ATR inhibition. ATR promotes homologous recombination DNA repair and inter-strand cross-link repair. Impairment of ATR function by genetic means or with inhibitors increases the sensitivity of cells to a wide variety of DNA damaging chemotherapy and radiotherapy, with the greatest sensitization observed with gemcitabine and cisplatin. Early inhibitors developed in the 1990s were weak and non-specific but the encouraging data led to the development of more potent and specific inhibitors. We review here the pre-clinical chemo- and radiosensitisation data obtained with these inhibitors that has led to the entry into clinical trial, the potential to combine ATR inhibitors with other DNA repair modulators, and identification of single-agent ATR inhibitor cytotoxicity in cells with activated oncogenes and particular defects in the DDR that may result in greater replication stress or dependence on ATR for survival.


Ataxia Telangiectasia Mutated and RAD3 related (ATR) ATR inhibitor Cell cycle checkpoint Replication stress DNA repair 


  1. Babior BM (1999) NADPH oxidase: an update. Blood 93(5):1464–1476PubMedPubMedCentralGoogle Scholar
  2. Bartkova J, Tommiska J, Oplustilova L, Aaltonen K, Tamminen A, Heikkinen T, Mistrik M, Aittomäki K, Blomqvist C, Heikkilä P, Lukas J, Nevanlinna H, Bartek J (2008) Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene. Mol Oncol 2:296–316PubMedPubMedCentralCrossRefGoogle Scholar
  3. Berasain C, Castillo J, Perugorria MJ, Latasa MU, Prieto J, Avila MA (2009) Inflammation and liver cancer: new molecular links. Ann N Y Acad Sci 1155:206–221PubMedCrossRefPubMedCentralGoogle Scholar
  4. Boultwood J (2001) Ataxia telangiectasia gene mutations in leukaemia and lymphoma. J Clin Pathol 54(7):512–516PubMedPubMedCentralCrossRefGoogle Scholar
  5. Brown EJ, Baltimore D (2000) ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev 14:397–402PubMedPubMedCentralGoogle Scholar
  6. Brown AD, Sager BW, Gorthi A, Tonapi SS, Brown EJ, Bishop AJR (2014) ATR suppresses endogenous DNA damage and allows completion of homologous recombination repair. PLoS One 9(3):e91222. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bryant HE, Petermann E, Schultz N, Jemth AS, Loseva O, Issaeva N, Johansson F, Fernandez S, McGlynn P, Helleday T (2009) PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination. EMBO J 28(17):2601–2615PubMedPubMedCentralCrossRefGoogle Scholar
  8. Burdova K, Mihaljevic B, Sturzenegger A, Chappidi N, Janscak P (2015) The mismatch-binding factor MutSbeta can mediate ATR activation in response to DNA double-strand breaks. Mol Cell 59(4):603–614PubMedCrossRefPubMedCentralGoogle Scholar
  9. Caldecott KW (2003) XRCC1 and DNA strand break repair. DNA Repair 2(9):955–969PubMedCrossRefPubMedCentralGoogle Scholar
  10. Cancer Genome Atlas Network (2012a) Comprehensive molecular portraits of human breast tumours. Nature 490:61–80CrossRefGoogle Scholar
  11. Cancer Genome Atlas Network (2012b) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489:519–525CrossRefGoogle Scholar
  12. Caporali S, Falcinelli S, Starace G, Russo MT, Bonmassar E, Jiricny J, D’Atri S (2004) DNA damage induced by temozolomide signals to both ATM and ATR: role of the mismatch repair system. Mol Pharmacol 66(3):478–491PubMedPubMedCentralGoogle Scholar
  13. Caporali S, Levati L, Starace G, Ragone G, Bonmassar E, Alvino E, D’Atri S (2008) AKT is activated in an ataxia-telangiectasia and Rad3-related-dependent manner in response to temozolomide and confers protection against drug-induced cell growth inhibition. Mol Pharmacol 74(1):173–183PubMedCrossRefPubMedCentralGoogle Scholar
  14. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404PubMedCrossRefPubMedCentralGoogle Scholar
  15. Charrier JD, Durrant SJ, Golec JM, Kay DP, Knegtel RM, MacCormick S Mortimore M, O’Donnell ME, Pinder JL, Reaper PM, Rutherford AP, Wang PS, Young SC, Pollard JR (2011) Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem 54:2320–2330PubMedCrossRefPubMedCentralGoogle Scholar
  16. Chen MS, Ryan CE, Piwnica-Worms H (2003) CHK1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding. Mol Cell Biol 23(21):7488–7497PubMedPubMedCentralCrossRefGoogle Scholar
  17. Choi JH, Lindsey-Boltz LA, Kemp M, Mason AC, Wold MS, Sancar A (2010) Reconstitution of RPA-covered single-stranded DNA-activated ATR-CHK1 signaling. Proc Natl Acad Sci U S A 107(31):13660–13665PubMedPubMedCentralCrossRefGoogle Scholar
  18. Cleaver JE (2016) Profile of Thomas Lindahl, Paul Modrich ans Aziz Sancar, 2015 Noel Laureates in chemistry. Proc Natl Acad Sci U S A 113(2):242–245PubMedCrossRefPubMedCentralGoogle Scholar
  19. Cliby WA, Roberts CJ, Cimprich KA, Stringer CM, Lamb JR, Schreiber SL, Friend SH (1998) Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J 17(1):159–169PubMedPubMedCentralCrossRefGoogle Scholar
  20. Cliby WA, Lewis KA, Lilly KK, Kaufmann SH (2002) S phase and G2 arrests induced by topoisomerase I poisons are dependent on ATR kinase function. J Biol Chem 277(2):1599–1606PubMedCrossRefPubMedCentralGoogle Scholar
  21. Cole AJ, Dwight T, Gill AJ, Dickson KA, Zhu Y, Clarkson A, Gard GB, Maidens J, Valmadre S, Clifton-Bligh R, Marsh DJ (2016) Assessing mutant p53 in primary high-grade serous ovarian cancer using immunohistochemistry and massively parallel sequencing. Sci Rep 6:26191PubMedPubMedCentralCrossRefGoogle Scholar
  22. Collis SJ, Swartz MJ, Nelson WG, DeWeese TL (2003) Enhanced radiation and chemotherapy-mediated cell killing of human cancer cells by small inhibitory RNA silencing of DNA repair factors. Cancer Res 63(7):1550–1554PubMedPubMedCentralGoogle Scholar
  23. Collis SJ, Ciccia A, Deans AJ, Horejsi Z, Martin JS, Maslen SL, Skehel JM, Elledge SJ, West SC, Boulton SJ (2008) FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex. Mol Cell 32(3):313–324PubMedCrossRefPubMedCentralGoogle Scholar
  24. Cortez D (2003) Caffeine inhibits checkpoint responses without inhibiting the ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) protein kinases. J Biol Chem 278(39):37139–37145PubMedCrossRefPubMedCentralGoogle Scholar
  25. Cottini F, Hideshima T, Suzuki R, Tai YT, Bianchini G, Richardson PG, Anderson KC, Tonon G (2015) Synthetic lethal approaches exploiting DNA damage in aggressive myeloma. Cancer Discov 5(9):972–987PubMedPubMedCentralCrossRefGoogle Scholar
  26. Couch FB, Bansbach CE, Driscoll R, Luzwick JW, Glick GG, Bétous R, Carroll CM, Jung SY, Qin J, Cimprich KA, Cortez D (2013) ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Genes Dev 27(14):1610–1623PubMedPubMedCentralCrossRefGoogle Scholar
  27. Cox KE, Marechal A, Flynn RL (2016) SMARCAL1 resolves replication stress at ALT telomeres. Cell Rep 14:1032–1040PubMedPubMedCentralCrossRefGoogle Scholar
  28. Cui Y, Palii SS, Innes CL, Paules RS (2014) Depletion of ATR selectively sensitizes ATM-deficient human mammary epithelial cells to ionizing radiation and DNA-damaging agents. Cell Cycle 13(22):3541–3550PubMedPubMedCentralCrossRefGoogle Scholar
  29. Curtin NJ (2014) PARP inhibitors for anticancer Therapy. Biochem Soc Trans 42:82–88PubMedCrossRefPubMedCentralGoogle Scholar
  30. Dai Y, Grant S (2010) New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res 16(2):376–383PubMedPubMedCentralCrossRefGoogle Scholar
  31. Dart DA, Adams KE, Akerman I, Lakin ND (2004) Recruitment of the cell cycle checkpoint kinase ATR to chromatin during S-phase. J Biol Chem 269:16433–16440CrossRefGoogle Scholar
  32. Davidson IF, Li A, Blow JJ (2006) Deregulated replication licensing causes DNA fragmentation consistent with head-to-tail fork collision. Mol Cell 24:433–443PubMedPubMedCentralCrossRefGoogle Scholar
  33. Deans AJ, West SC (2011) DNA interstrand crosslink repair and cancer. Nat Rev Cancer 24:467–480CrossRefGoogle Scholar
  34. Deeg KI, Chung I, Bauer C, Rippe K (2016) Cancer Cells with Alternative Lengthening of Telomeres Do Not Display a General Hypersensitivity to ATR Inhibition. Front Oncol 6:186. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Dominguez-Sola D, Ying CY, Grandori C, Ruggiero L, Chen B, Li M, Galloway DA, Gu W, Gautier J, Dalla-Favera R (2007) Non-transcriptional control of DNA replication by c-Myc. Nature 448:445–451PubMedPubMedCentralCrossRefGoogle Scholar
  36. Draskovic I, Londono-Vallejo A (2014) Telomere recombination and the ALT pathway: a therapeutic perspective for cancer. Curr Pharm Des 20:6466–6471PubMedCrossRefPubMedCentralGoogle Scholar
  37. Durocher D, Jackson SP (2001) DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr Opin Cell Biol 13(2):225–231PubMedCrossRefPubMedCentralGoogle Scholar
  38. Eich M, Roos WP, Nikolova T, Kaina B (2013) Contribution of ATM and ATR to the resistance of glioblastoma and malignant melanoma cells to the methylating anticancer drug temozolomide. Mol Cancer Ther 12(11):2529–2540PubMedCrossRefPubMedCentralGoogle Scholar
  39. Fang WH, Li GM, Longley M, Holmes J, Thilly W, Modrich P (1993) Mismatch repair and genetic stability in human cells. Cold Spring Harb Symp Quant Biol 58:597–603PubMedCrossRefPubMedCentralGoogle Scholar
  40. Flatten K, Dai NT, Vroman BT, Loegering D, Erlichman C, Karnitz LM, Kaufmann SH (2005) The role of checkpoint kinase 1 in sensitivity to topoisomerase I poisons. J Biol Chem 280(14):14349–14355PubMedCrossRefPubMedCentralGoogle Scholar
  41. Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, Bersani F, Pineda JR, Suva ML, Benes CH et al (2015) Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 347:273–277PubMedPubMedCentralCrossRefGoogle Scholar
  42. Fokas E, Prevo R, Pollard JR, Reaper PM, Charlton PA, Cornelissen B, Vallis KA, Hammond EM, Olcina MM, Gillies McKenna W, Muschel RJ, Brunner TB (2012) Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis 3:e441PubMedPubMedCentralCrossRefGoogle Scholar
  43. Foote KM, Blades K, Cronin A, Fillery S, Guichard SS, Hassall L, Hickson I, Jacq X, Jewsbury PJ, McGuire TM, Nissink JW, Odedra R, Page K, Perkins P, Suleman A, Tam K, Thommes P, Broadhurst R, Wood C (2013) Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity. J Med Chem 56(5):2125–2138PubMedCrossRefPubMedCentralGoogle Scholar
  44. Foote KM, Lau A, Nissink JW (2015) Drugging ATR: progress in the development of specific inhibitors for the treatment of cancer. Future Med Chem 7:873–891PubMedCrossRefPubMedCentralGoogle Scholar
  45. Gaillard H, García-Muse T, Aguilera A (2015) Replication stress and cancer. Nat Rev Cancer 15:276–289PubMedCrossRefPubMedCentralGoogle Scholar
  46. Genschel J, Modrich P (2009) Functions of MutLalpha, replication protein A (RPA), and HMGB1 in 5′-directed mismatch repair. J Biol Chem 284(32):21536–21544PubMedPubMedCentralCrossRefGoogle Scholar
  47. Gilad O, Nabet BY, Ragland RL, Schoppy DW, Smith KD, Durham AC, Brown EJ (2010) Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Res 70(23):9693–9702PubMedPubMedCentralCrossRefGoogle Scholar
  48. Guichard SM, Brown E, Odedra R, Hughes A, Heathcote D, Barnes J, Lau A, Powell S, Jones CD, Nissink JW, Foote KM, Jewsbury PJ, Pass M (2013) The pre-clinical in vitro and in vivo activity of AZD6738: a potent and selective inhibitor of ATR kinase. Cancer Res 73(8 Suppl):Abstract nr 3343CrossRefGoogle Scholar
  49. Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319:1352–1355PubMedCrossRefPubMedCentralGoogle Scholar
  50. Hall AB, Newsome D, Wang Y, Boucher DM, Eustace B, Gu Y, Hare B, Johnson MA, Milton S, Murphy CE, Takemoto D, Tolman C, Wood M, Charlton P, Charrier JD, Furey B, Golec J, Reaper PM, Pollard JR (2014) Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970. Oncotarget 5:5674–5685PubMedPubMedCentralCrossRefGoogle Scholar
  51. Hammond EM, Giaccia AJ (2004) The role of ATM and ATR in the cellular response to hypoxia and re-oxygenation. DNA Repair (Amst). 3(8-9):1117–1122PubMedCrossRefPubMedCentralGoogle Scholar
  52. Hammond EM, Dorie MJ, Giaccia AJ (2004) Inhibition of ATR leads to increased sensitivity to hypoxia/reoxygenation. Cancer Res 64(18):6556–6562PubMedCrossRefPubMedCentralGoogle Scholar
  53. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674PubMedCrossRefPubMedCentralGoogle Scholar
  54. Haynes B, Saadat N, Myung B, Shekhar MP (2015) Crosstalk between translesion synthesis, Fanconi anemia network, and homologous recombination repair pathways in interstrand DNA crosslink repair and development of chemoresistance. Mutat Res 763:258–266CrossRefGoogle Scholar
  55. Hocke S, Guo Y, Job A, Orth M, Ziesch A, Lauber K, De Toni EN, Gress TM, Herbst A, Göke B, Gallmeier EA (2016) synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers. Oncotarget 7(6):7080–7095PubMedPubMedCentralCrossRefGoogle Scholar
  56. Huntoon CJ, Flatten KS, Wahner Hendrickson AE, Huehls AM, Sutor SL, Kaufmann SH, Karnitz LM (2013) ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status. Cancer Res 73(12):3683–3691PubMedPubMedCentralCrossRefGoogle Scholar
  57. Hurley PJ, Wilsker D, Bunz F (2007) Human cancer cells require ATR for cell cycle progression following exposure to ionizing radiation. Oncogene 26(18):2535–2542PubMedCrossRefPubMedCentralGoogle Scholar
  58. Itakura E, Umeda K, Sekoguchi E, Takata H, Ohsumi M, Matsuura A (2004) ATR-dependent phosphorylation of ATRIP in response to genotoxic stress. Biochem Biophys Res Commun 323(4):1197–1202PubMedCrossRefPubMedCentralGoogle Scholar
  59. Jiang H, Reinhardt HC, Bartkova J, Tommiska J, Blomqvist C, Nevanlinna H, Bartek J, Yaffe MB, Hemann MT (2009) The combined status of ATM and p53 link tumor development with therapeutic response. Genes Dev 23:1895–1909PubMedPubMedCentralCrossRefGoogle Scholar
  60. Jones CD, Blades K, Foote KM, Guichard SM, Jewsbury PJ, McGuire T, Nissink JW, Odedra R, Tam K, Thommes P, Turner P, Wilkinson G, Wood C, Yates JW (2013) Discovery of AZD6738, a potent and selective inhibitor with the potential to test the clinical efficacy of ATR kinase inhibition in cancer patients. [abstract]. Cancer Res 73(8 Suppl):Abstract nr 2348CrossRefGoogle Scholar
  61. Jossé R, Martin SE, Guha R, Ormanoglu P, Pfister TD, Reaper PM, Barnes CS, Jones J, Charlton P, Pollard JR, Morris J, Doroshow JH, Pommier Y (2014) ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res 74(23):6968–6979PubMedPubMedCentralCrossRefGoogle Scholar
  62. Kedar PS, Stefanick DF, Horton JK, Wilson SH (2008) Interaction between PARP-1 and ATR in mouse fibroblasts is blocked by PARP inhibition. DNA Repair (Amst) 7(11):1787–1798CrossRefGoogle Scholar
  63. Kim H, D’Andrea AD (2012) Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway. Genes Dev 26:1393–1408PubMedPubMedCentralCrossRefGoogle Scholar
  64. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T, Weiss WA, Williams RL, Shokat KM (2006) A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125(4):733–747PubMedPubMedCentralCrossRefGoogle Scholar
  65. Krajewska M, Fehrmann RS, Schoonen PM, Labib S, de Vries EG, Franke L, van Vugt MA (2015) ATR inhibition preferentially targets homologous recombination-deficient tumor cells. Oncogene 34(26):3474–3481PubMedCrossRefPubMedCentralGoogle Scholar
  66. Kwok M, Davies N, Agathanggelou A, Smith E, Oldreive C, Petermann E, Stewart G, Brown J, Lau A, Pratt G, Parry H, Taylor M, Moss P, Hillmen P, Stankovic T (2016) ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. Blood 127(5):582–595PubMedCrossRefPubMedCentralGoogle Scholar
  67. Lau A, Brown E, Thomason A, Odedra R, Sheridan V, Cadogan E, Xu S, Cui A, Gavine PR, O’Connor M (2015) Pre-clinical efficacy of the ATR inhibitor AZD6738 in combination with the PARP inhibitor olaparib. Mol Cancer Ther 14(12 Suppl 2):Abstract nr C60CrossRefGoogle Scholar
  68. Lee J, Kumagai A, Dunphy WG (2001) Positive regulation of Wee1 by CHK1 and 14-3-3 proteins. Mol Biol Cell 12(3):551–563PubMedPubMedCentralCrossRefGoogle Scholar
  69. Lee KW, Tsai YS, Chiang FY, Huang JL, Ho KY, Yang YH, Kuo WR, Chen MK, Lin CS (2011) Lower ataxia telangiectasia mutated (ATM) mRNA expression is correlated with poor outcome of laryngeal and pharyngeal cancer patients. Ann Oncol 22:1088–1093PubMedCrossRefPubMedCentralGoogle Scholar
  70. Li M, Yu X (2015) The role of poly(ADP-ribosyl)ation in DNA damage response and cancer chemotherapy. Oncogene 34(26):3349–3356PubMedCrossRefPubMedCentralGoogle Scholar
  71. Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362(6422):709–715PubMedCrossRefPubMedCentralGoogle Scholar
  72. Lindsey-Boltz LA, Sancar A (2011) Tethering DNA damage checkpoint mediator proteins topoisomerase IIbeta-binding protein 1 (TopBP1) and Claspin to DNA activates ataxia-telangiectasia mutated and RAD3-related (ATR) phosphorylation of checkpoint kinase 1 (CHK1). J Biol Chem 286(22):19229–19236PubMedPubMedCentralCrossRefGoogle Scholar
  73. Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F, Bradley A, Donehower LA, Elledge SJ (2000) CHK1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev 14(12):1448–1459PubMedPubMedCentralGoogle Scholar
  74. Liu Y, Fang Y, Shao H, Lindsey-Boltz L, Sancar A, Modrich P (2010) Interactions of human mismatch repair proteins MutSalpha and MutLalpha with proteins of the ATR-CHK1 pathway. J Biol Chem 285(8):5974–5982PubMedCrossRefPubMedCentralGoogle Scholar
  75. Lomax ME, Folkes LK, O’Neill P (2013) Biological consequences of radiation-induced DNA damage: relevance to radiotherapy. Clin Oncol 25:578–585CrossRefGoogle Scholar
  76. Luciani MG, Oehlmann M, Blow JJ (2004) Characterization of a novel ATR-dependent, Chk1-independent, intra-S-phase checkpoint that suppresses initiation of replication in Xenopus. J Cell Sci 117(Pt 25):6019–6030PubMedPubMedCentralCrossRefGoogle Scholar
  77. Luke-Glaser S, Luke B, Grossi S, Constantinou A (2010) FANCM regulates DNA chain elongation and is stabilized by S-phase checkpoint signalling. EMBO J 29(4):795PubMedCrossRefPubMedCentralGoogle Scholar
  78. Macheret M, Halazonetis TD (2015) DNA replication stress as a hallmark of cancer. Annu Rev Pathol 10:425–448PubMedCrossRefPubMedCentralGoogle Scholar
  79. Mackay DR, Ullman KS (2015) ATR and a CHK1-Aurora B pathway coordinate postmitotic genome surveillance with cytokinetic abscission. Mol Biol Cell 26(12):2217–2226PubMedPubMedCentralCrossRefGoogle Scholar
  80. Mailand N, Falck J, Lukas C, Syljuasen RG, Welcker M, Bartek J, Lukas J (2000) Rapid destruction of human Cdc25A in response to DNA damage. Science 288(5470):1425–1429PubMedCrossRefPubMedCentralGoogle Scholar
  81. Marteijn JA, Lans H, Vermeulen W, Hoeijmakers JH (2014) Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol 15(7):465–481PubMedCrossRefPubMedCentralGoogle Scholar
  82. Massague J (2004) G1 cell-cycle control and cancer. Nature 432(7015):298–306PubMedCrossRefPubMedCentralGoogle Scholar
  83. Masters JRW, Koberle B (2003) Curing metastatic cancer: lessons from testicular germ-cell tumours. Nat Rev Cancer 3:517–525PubMedCrossRefPubMedCentralGoogle Scholar
  84. Matsuoka S, Ballif BA, Smogorzewska A, ER MD III, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316(5828):1160–1166PubMedCrossRefPubMedCentralGoogle Scholar
  85. Menezes DL, Holt J, Tang Y, Feng J, Barsanti P, Pan Y, Ghoddusi M, Zhang W, Thomas G, Holash J, Lees E, Taricani L (2015) A synthetic lethal screen reveals enhanced sensitivity to ATR inhibitor treatment in mantle cell lymphoma with ATM loss-of-function. Mol Cancer Res 13(1):120–129PubMedCrossRefPubMedCentralGoogle Scholar
  86. Middleton FK, Patterson MJ, Elstob CJ, Fordham S, Herriott A, Wade MA, McCormick A, Edmondson R, May FE, Allan JM, Pollard JR, Common CNJ (2015) cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition. Oncotarget 6(32):32396–32409PubMedPubMedCentralCrossRefGoogle Scholar
  87. Mlasenov E, Mahin S, Soni A, Illiakis G (2016) DNA double-strand-break repair in higher eukaryotes and its role in genomic instability and cancer: cell cycle and proliferation-dependent regulation. Semin Cancer Biol 37-38:51–64CrossRefGoogle Scholar
  88. Mohni KN, Kavanaugh GM, Cortez D (2014) ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency. Cancer Res 74(10):2835–2845. CrossRefPubMedPubMedCentralGoogle Scholar
  89. Mohni KN, Thompson PS, Luzwick JW, Glick GG, Pendleton CS, Lehmann BD, Pietenpol JA, Cortez DA (2015) Synthetic lethal screen identifies DNA repair pathways that sensitize cancer cells to combined ATR inhibition and cisplatin treatments. PLoS One 10(5):e0125482PubMedPubMedCentralCrossRefGoogle Scholar
  90. Moiseeva O, Bourdeau V, Roux A, Deschenes-Simard X, Ferbeyre G (2009) Mitochondrial dysfunction contributes to oncogene-induced senescence. Mol Cell Biol 29:4495–4507PubMedPubMedCentralCrossRefGoogle Scholar
  91. Morishima K, Sakamoto S, Kobayashi J, Izumi H, Suda T, Matsumoto Y, Tauchi H, Ide H, Komatsu K, Matsuura S (2007) TopBP1 associates with NBS1 and is involved in homologous recombination repair. Biochem Biophys Res Commun 362(4):872–879PubMedCrossRefPubMedCentralGoogle Scholar
  92. Moser J, Kool H, Giakzidis I, Caldecott K, Mullenders LH, Fousteri MI (2007) Sealing of chromosomal DNA nicks during nucleotide excision repair requires XRCC1 and DNA ligase III alpha in a cell-cycle-specific manner. Mol Cell 27(2):311–323PubMedCrossRefPubMedCentralGoogle Scholar
  93. Murga M, Bunting S, Montaña MF, Soria R, Mulero F, Cañamero M, Lee Y, McKinnon PJ, Nussenzweig A, Fernandez-Capetillo O (2009) A mouse model of ATRSeckel shows embryonic replicative stress and accelerated aging. Nat Genet 41:891–899PubMedPubMedCentralCrossRefGoogle Scholar
  94. Murga M, Campaner S, Lopez-Contreras AJ, Toledo LI, Soria R, Montaña MF, D’Artista L, Schleker T, Guerra C, Garcia E, Barbacid M, Hidalgo M, Amati B, Fernandez-Capetillo O (2011) Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat Struct Mol Biol 18(12):1331–1335PubMedPubMedCentralCrossRefGoogle Scholar
  95. Myers K, Gagou ME, Zuazua-Villar P, Rodriguez R, Meuth M (2009) ATR and Chk1 suppress a caspase-3–dependent apoptotic response following DNA replication stress. PLoS Genet 5(1):e1000324. CrossRefPubMedPubMedCentralGoogle Scholar
  96. Nghiem P, Park PK, Kim YS, Vaziri C, Schreiber SL (2001) ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal premature chromatin condensation. Proc Natl Acad Sci U S A 98(16):9092–9097PubMedPubMedCentralCrossRefGoogle Scholar
  97. Nghiem P, Park PK, Kim Ys YS, Desai BN, Schreiber SL (2002) ATR is not required for p53 activation but synergizes with p53 in the replication checkpoint. J Biol Chem 277(6):4428–4434PubMedCrossRefPubMedCentralGoogle Scholar
  98. Nishida H, Tatewaki N, Nakajima Y, Magara T, Ko KM, Hamamori Y, Konishi T (2009) Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response. Nucleic Acids Res 37(17):5678–5689PubMedPubMedCentralCrossRefGoogle Scholar
  99. O’Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA (2003) A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33(4):497–501PubMedCrossRefPubMedCentralGoogle Scholar
  100. O’Driscoll M, Gennery AR, Seidel J, Concannon P, Jeggo PA (2004) An overview of three new disorders associated with genetic instability: LIG4 syndrome, RS-SCID and ATR-Seckel syndrome. DNA Repair (Amst) 3(8-9):1227–1235CrossRefGoogle Scholar
  101. Olivier M, Hollstein M, Hainaut P (2010) TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2(1):a001008PubMedPubMedCentralCrossRefGoogle Scholar
  102. Parsels LA, Qian Y, Tanska DM, Gross M, Zhao L, Hassan MC, Arumugarajah S, Parsels JD, Hylander-Gans L, Simeone DM, Morosini D, Brown JL, Zabludoff SD, Maybaum J, Lawrence TS, Morgan MA (2011) Assessment of CHK1 phosphorylation as a pharmacodynamic biomarker of CHK1 inhibition. Clin Cancer Res 17(11):3706–3715PubMedPubMedCentralCrossRefGoogle Scholar
  103. Patch AM, Christie EL, Etemadmoghadam D, Garsed DW, George J, Fereday S, Nones K, Cowin P, Alsop K, Bailey PJ, Kassahn KS, Newell F, Quinn MC, Kazakoff S, Quek K, Wilhelm-Benartzi C, Curry E, Leong HS (2015) Australian Ovarian Cancer Study Group, et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 521:489–494PubMedCrossRefPubMedCentralGoogle Scholar
  104. Peasland A, Wang LZ, Rowling E, Kyle S, Chen T, Hopkins A, Cliby WA, Sarkaria J, Beale G, Edmondson RJ, Curtin NJ (2011) Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines. Br J Cancer 105(3):372–381PubMedPubMedCentralCrossRefGoogle Scholar
  105. Pires IM, Olcina MM, Anbalagan S, Pollard JR, Reaper PM, Charlton PA, McKenna WG, Hammond EM (2012) Targeting radiation-resistant hypoxic tumour cells through ATR inhibition. Br J Cancer 107(2):291–299PubMedPubMedCentralCrossRefGoogle Scholar
  106. Pollard J, Reaper P, Peek A, Hughes S, Gladwell S, Jones J, Chiu P, Wood M, Tolman C, Johnson M, Littlewood P, Penney M, McDermott K, Hare B, Fields SZ, Asmal M, O’Carrigan B, Yap TA (2016a) Defining optimal dose schedules for ATR inhibitors in combination with DNA damaging drugs: informing clinical studies of VX-970, the first-in-class ATR inhibitor. Cancer Res 76(14 Suppl):Abstract nr 3717CrossRefGoogle Scholar
  107. Pollard J, Reaper P, Peek A, Hughes S, Dheja H, Cummings S, Larbi K, Penney M, Sullivan J, Takemoto D, Defranco C (2016b) Pre-clinical combinations of ATR and PARP inhibitors: defining target patient populations and dose schedule. Cancer Res 76(14 Suppl):Abstract nr 3711CrossRefGoogle Scholar
  108. Prevo R, Fokas E, Reaper PM, Charlton PA, Pollard JR, McKenna WG, Muschel RJ, Brunner TB (2012) The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther 13(11):1072–1081PubMedPubMedCentralCrossRefGoogle Scholar
  109. Reaper PM, Griffiths MR, Long JM, Charrier JD, Maccormick S, Charlton PA, Golec JM, Pollard JR (2011) Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol 7(7):428–430PubMedCrossRefPubMedCentralGoogle Scholar
  110. Ringborg U, Bergqvist D, Brorsson B, Cavallin-Ståhl E, Ceberg J, Einhorn N, Frödin JE, Järhult J, Lamnevik G, Lindholm C, Littbrand B, Norlund A, Nylén U, Rosén M, Svensson H, Möller TR (2003) The Swedish Council on Technology Assessment in Health Care (SBU) systematic overview of radiotherapy for cancer including a prospective survey of radiotherapy practice in Sweden 2001 — summary and conclusions. Acta Oncol 42:357–365PubMedCrossRefPubMedCentralGoogle Scholar
  111. Ruzankina Y, Pinzon-Guzman C, Asare A, Ong T, Pontano L, Cotsarelis G, Zediak VP, Velez M, Bhandoola A, Deletion BEJ (2007) of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. Cell Stem Cell 1:113–126PubMedPubMedCentralCrossRefGoogle Scholar
  112. Sangster-Guity N, Conrad BH, Papadopoulos N, Bunz F (2011) ATR mediates cisplatin resistance in a p53 genotype-specific manner. Oncogene 30(22):2526–2533PubMedPubMedCentralCrossRefGoogle Scholar
  113. Sanjiv K, Hagenkort A, Calderón-Montaño JM, Koolmeister T, Reaper PM, Mortusewicz O, Jacques SA, Kuiper RV, Schultz N, Scobie M, Charlton PA, Pollard JR, Berglund UW, Altun M, Helleday T (2016) Cancer-specific synthetic lethality between ATR and CHK1 kinase activities. Cell Rep 14(2):298–309PubMedCrossRefPubMedCentralGoogle Scholar
  114. Sarkaria JN, Busby EC, Tibbetts RS, Roos P, Taya Y, Karnitz LM, Abraham RT (1999) Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res 59(17):4375–4382PubMedPubMedCentralGoogle Scholar
  115. Schaffner C, Stilgenbauer S, Rappold GA, Döhner H, Lichter P, Somatic ATM (1999) mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia. Blood 94(2):748–753PubMedPubMedCentralGoogle Scholar
  116. Schoppy DW, Ragland RL, Gilad O, Shastri N, Peters AA, Murga M et al (2012) Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR. J Clin Invest 122:241–252PubMedCrossRefPubMedCentralGoogle Scholar
  117. Schwab RA, Blackford AN, Niedzwiedz W (2010) ATR activation and replication fork restart are defective in FANCM-deficient cells. EMBO J 29(4):806–818PubMedPubMedCentralCrossRefGoogle Scholar
  118. Shiotani B, Zou L (2009) Single-stranded DNA orchestrates an ATM-to-ATR switch at DNA breaks. Mol Cell 33(5):547–558PubMedPubMedCentralCrossRefGoogle Scholar
  119. Sibghatullah HI, Carlton W, Sancar A (1989) Human nucleotide excision repair in vitro: repair of pyrimidine dimers, psoralen and cisplatin adducts by HeLa cell-free extract. Nucleic Acids Res 17(12):4471–4484PubMedPubMedCentralCrossRefGoogle Scholar
  120. Singh TR, Ali AM, Paramasivam M, Pradhan A, Wahengbam K, Seidman MM, Meetei AR (2013) ATR-dependent phosphorylation of FANCM at serine 1045 is essential for FANCM functions. Cancer Res 73(14):4300–4310PubMedPubMedCentralCrossRefGoogle Scholar
  121. Sorensen CS, Syljuasen RG (2012) Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication. Nucleic Acids Res 40(2):477–486PubMedCrossRefPubMedCentralGoogle Scholar
  122. Sorensen CS, Syljuasen RG, Falck J, Schroeder T, Ronnstrand L, Khanna KK, Zhou BB, Bartek J, Lukas J (2003) CHK1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell 3(3):247–258PubMedCrossRefPubMedCentralGoogle Scholar
  123. Sorensen CS, Syljuasen RG, Lukas J, Bartek J (2004) ATR, Claspin and the Rad9-Rad1-Hus1 complex regulate CHK1 and Cdc25A in the absence of DNA damage. Cell Cycle 3(7):941–945PubMedCrossRefPubMedCentralGoogle Scholar
  124. Storz P (2005) Reactive oxygen species in tumor progression. Front Biosci 10:1881–1896PubMedCrossRefPubMedCentralGoogle Scholar
  125. Sugimura K, Takebayashi S, Taguchi H, Takeda S, Okumura K (2008) PARP-1 ensures regulation of replication fork progression by homologous recombination on damaged DNA. J Cell Biol 183(7):1203–1212PubMedPubMedCentralCrossRefGoogle Scholar
  126. Sultana R, Abdel-Fatah T, Perry C, Moseley P, Albarakti N, Mohan V, Seedhouse C, Chan S, Madhusudan S (2013) Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells. PLoS One 8(2):e57098PubMedPubMedCentralCrossRefGoogle Scholar
  127. Symington LS, Gautier J (2011) Double-strand break end resection and repair pathway choice. Annu Rev Genet 45:247–271PubMedCrossRefPubMedCentralGoogle Scholar
  128. Taylor EM, Lindsay HD (2016) DNA replication stress and cancer: cause or cure? Future Oncol 12:221–237PubMedCrossRefPubMedCentralGoogle Scholar
  129. Teng PN, Bateman NW, Darcy KM, Hamilton CA, Maxwell GL, Bakkenist CJ, Conrads TP (2015) Pharmacologic inhibition of ATR and ATM offers clinically important distinctions to enhancing platinum or radiation response in ovarian, endometrial, and cervical cancer cells. Gynecol Oncol 136(3):554–561PubMedPubMedCentralCrossRefGoogle Scholar
  130. The Cancer Genome Atlas Research Network (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474:609–615PubMedCentralCrossRefGoogle Scholar
  131. Toledo LI, Murga M, Zur R, Soria R, Rodriguez A, Martinez S, Oyarzabal J, Pastor J, Bischoff JR, Fernandez-Capetillo O (2011) A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol 18(6):721–727PubMedPubMedCentralCrossRefGoogle Scholar
  132. Toledo LI, Altmeyer M, Rask MB, Lukas C, Larsen DH, Povlsen LK, Bekker-Jensen S, Mailand N, Bartek J, Lukas J (2013) ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell 155(5):1088–1103PubMedCrossRefPubMedCentralGoogle Scholar
  133. Tomida J, Itaya A, Shigechi T, Unno J, Uchida E, Ikura M, Masuda Y, Matsuda S, Adachi J, Kobayashi M, Meetei AR, Maehara Y, Yamamoto K, Kamiya K, Matsuura A, Matsuda T, Ikura T, Ishiai M, Takata M (2013) A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair. Nucleic Acids Res 41(14):6930–6941PubMedPubMedCentralCrossRefGoogle Scholar
  134. Tutt A, Ellis P, Kilburn L, Gilett C, Pinder S, Abraham J, Barrett S, Barrett-Lee P, Chan S, Cheang M, Fox L, Grigoriadis A, Harper-Wynne C, Hatton M, Kernaghan S, Owen J, Parker P, Rahman N, Roylance R, Smith I, Thompson R, Tovey H, Wardley A, Wilson G, Harries M, Bliss J (2015) The TNT trial: a randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). Cancer Res 75(9 Suppl):Abstract nr S3-01CrossRefGoogle Scholar
  135. Unsal-Kacmaz K, Sancar A (2004) Quaternary structure of ATR and effects of ATRIP and replication protein A on its DNA binding and kinase activities. Mol Cell Biol 24(3):1292–1300PubMedPubMedCentralCrossRefGoogle Scholar
  136. Usanova S, Piée-Staffa A, Sied U, Thomale J, Schneider A, Kaina B, Köberle B (2010) Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand-crosslink repair and low ERCC1-XPF expression. Mol Cancer 9:248PubMedPubMedCentralCrossRefGoogle Scholar
  137. Vendetti FP, Lau A, Schamus S, Conrads TP, O’Connor MJ, Bakkenist CJ (2015) The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. Oncotarget 6(42):44289–44305PubMedPubMedCentralCrossRefGoogle Scholar
  138. Wagner JM, Karnitz LM (2009) Cisplatin-induced DNA damage activates replication checkpoint signaling components that differentially affect tumour cell survival. Mol Pharmacol 76(1):208–214PubMedPubMedCentralCrossRefGoogle Scholar
  139. Wallace SS, Murphy DL, Sweasy JB (2012) Base excision repair and cancer. Cancer Lett 327(1-2):73–89PubMedPubMedCentralCrossRefGoogle Scholar
  140. Wang Y, Qin J (2003) MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation. Proc Natl Acad Sci U S A 100(26):15387–15392PubMedPubMedCentralCrossRefGoogle Scholar
  141. Wang H, Wang H, Powell SN, Iliakis G, Wang Y (2004) ATR affecting cell radiosensitivity is dependent on homologous recombination repair but independent of nonhomologous end joining. Cancer Res 64(19):7139–7143PubMedCrossRefPubMedCentralGoogle Scholar
  142. Weber AM, Drobnitzky N, Devery AM, Bokobza SM, Adams RA, Maughan TS, Ryan AJ (2016) Phenotypic consequences of somatic mutations in the ataxia-telangiectasia mutated gene in non-small cell lung cancer. Oncotarget 7(38):60807. CrossRefPubMedPubMedCentralGoogle Scholar
  143. Wilsker D, Bunz F (2007) Loss of ataxia telangiectasia mutated- and Rad3-related function potentiates the effects of chemotherapeutic drugs on cancer cell survival. Mol Cancer Ther 6(4):1406–1413PubMedCrossRefPubMedCentralGoogle Scholar
  144. Wilsker D, Chung JH, Pradilla I, Petermann E, Helleday T, Bunz F (2012) Targeted mutations in the ATR pathway define agent-specific requirements for cancer cell growth and survival. Mol Cancer Ther 11(1):98–107PubMedCrossRefPubMedCentralGoogle Scholar
  145. Wiseman H, Halliwell B (1996) Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J 313(Pt 1):17–29PubMedPubMedCentralCrossRefGoogle Scholar
  146. Wright JA, Keegan KS, Herendeen DR, Bentley NJ, Carr AM, Hoekstra MF, Concannon P (1998) Protein kinase mutants of human ATR increase sensitivity to UV and ionizing radiation and abrogate cell cycle checkpoint control. Proc Natl Acad Sci U S A 95(13):7445–7450PubMedPubMedCentralCrossRefGoogle Scholar
  147. Xiao Z, Chen Z, Gunasekera AH, Sowin TJ, Rosenberg SH, Fesik S, Zhang H (2003) CHK1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. J Biol Chem 278(24):21767–21773PubMedCrossRefPubMedCentralGoogle Scholar
  148. Yamane K, Taylor K, Kinsella TJ (2004) Mismatch repair-mediated G2/M arrest by 6-thioguanine involves the ATR-CHK1 pathway. Biochem Biophys Res Commun 318(1):297–302PubMedCrossRefPubMedCentralGoogle Scholar
  149. Yang XH, Shiotani B, Classon M, Zou L (2008) Chk1 and Claspin potentiate PCNA ubiquitination. Genes Dev 22(9):1147–1152PubMedPubMedCentralCrossRefGoogle Scholar
  150. Zhao H, Piwnica-Worms H (2001) ATR-mediated checkpoint pathways regulate phosphorylation and activation of human CHK1. Mol Cell Biol 21(13):4129–4139PubMedPubMedCentralCrossRefGoogle Scholar
  151. Zou L, Elledge SJ (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300(5625):1542–1548PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Northern Institute for Cancer Research, Medical SchoolNewcastle UniversityNewcastle upon TyneUK
  2. 2.Newcastle University Institute for Ageing, Medical SchoolNewcastle UniversityNewcastle upon TyneUK
  3. 3.Vertex Pharmaceuticals (Europe) LtdAbingdonUK

Personalised recommendations