Advertisement

Targeting ATR for Cancer Therapy: ATR-Targeted Drug Candidates

  • Magnus T. Dillon
  • Kevin J. Harrington
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

ATR inhibitors are a new class of anti-cancer compounds reaching early phase clinical trials. They are predicted to have anti-cancer activity as monotherapy, and in combination with DNA damaging chemotherapies and ionizing radiation. We outline the clinical trials in progress using the current clinical candidates VX-970 (M6620) and AZD6738, discuss potential biomarkers for this class of drug and consider future avenues for development of ATR inhibitors.

Keywords

Cell cycle checkpoint ATR inhibitor Radiosensitization Chemosensitization 

References

  1. Abdel-Fatah TM, Middleton FK, Arora A, Agarwal D, Chen T, Moseley PM, Perry C, Doherty R, Chan S, Green AR, Rakha E, Ball G, Ellis IO, Curtin NJ, Madhusudan S (2015) Untangling the ATR-CHEK1 network for prognostication, prediction and therapeutic target validation in breast cancer. Mol Oncol 9(3):569–585PubMedCrossRefPubMedCentralGoogle Scholar
  2. Ai L, Vo QN, Zuo C, Li L, Ling W, Suen JY, Hanna E, Brown KD, Fan CY (2004) Ataxia-telangiectasia-mutated (ATM) gene in head and neck squamous cell carcinoma: promoter hypermethylation with clinical correlation in 100 cases. Cancer Epidemiol Biomarkers Prev 13(1):150–156PubMedCrossRefPubMedCentralGoogle Scholar
  3. Al-Ahmadie H, Iyer G, Hohl M, Asthana S, Inagaki A, Schultz N, Hanrahan AJ, Scott SN, Brannon AR, McDermott GC, Pirun M, Ostrovnaya I, Kim P, Socci ND, Viale A, Schwartz GK, Reuter V, Bochner BH, Rosenberg JE, Bajorin DF, Berger MF, Petrini JH, Solit DB, Taylor BS (2014) Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy. Cancer Discov 4(9):1014–1021PubMedPubMedCentralCrossRefGoogle Scholar
  4. Angele S, Treilleux I, Taniere P, Martel-Planche G, Vuillaume M, Bailly C, Bremond A, Montesano R, Hall J (2000) Abnormal expression of the ATM and TP53 genes in sporadic breast carcinomas. Clin Cancer Res 6(9):3536–3544PubMedPubMedCentralGoogle Scholar
  5. Austen B, Powell JE, Alvi A, Edwards I, Hooper L, Starczynski J, Taylor AMR, Fegan C, Moss P, Stankovic T (2005) Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. Blood 106(9):3175–3182PubMedCrossRefPubMedCentralGoogle Scholar
  6. Austen B, Skowronska A, Baker C, Powell JE, Gardiner A, Oscier D, Majid A, Dyer M, Siebert R, Taylor AM, Moss PA, Stankovic T (2007) Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion. J Clin Oncol 25(34):5448–5457PubMedCrossRefPubMedCentralGoogle Scholar
  7. Bai AH, Tong JH, To KF, Chan MW, Man EP, Lo KW, Lee JF, Sung JJ, Leung WK (2004) Promoter hypermethylation of tumor-related genes in the progression of colorectal neoplasia. Int J Cancer 112(5):846–853PubMedCrossRefPubMedCentralGoogle Scholar
  8. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760PubMedCrossRefPubMedCentralGoogle Scholar
  9. Bartek J, Bartkova J, Lukas J (2007) DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 26(56):7773–7779PubMedCrossRefPubMedCentralGoogle Scholar
  10. Bester AC, Roniger M, Oren YS, Im MM, Sarni D, Chaoat M, Bensimon A, Zamir G, Shewach DS, Kerem B (2011) Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145(3):435–446PubMedPubMedCentralCrossRefGoogle Scholar
  11. Bhat A, Andersen PL, Qin Z, Xiao W (2013) Rev3, the catalytic subunit of Polzeta, is required for maintaining fragile site stability in human cells. Nucleic Acids Res 41(4):2328–2339PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bi X, Srikanta D, Fanti L, Pimpinelli S, Badugu R, Kellum R, Rong YS (2005) Drosophila ATM and ATR checkpoint kinases control partially redundant pathways for telomere maintenance. Proc Natl Acad Sci U S A 102(42):15167–15172PubMedPubMedCentralCrossRefGoogle Scholar
  13. Bolderson E, Scorah J, Helleday T, Smythe C, Meuth M (2004) ATM is required for the cellular response to thymidine induced replication fork stress. Hum Mol Genet 13(23):2937–2945PubMedCrossRefPubMedCentralGoogle Scholar
  14. Bolt J, Vo QN, Kim WJ, McWhorter AJ, Thomson J, Hagensee ME, Friedlander P, Brown KD, Gilbert J (2005) The ATM/p53 pathway is commonly targeted for inactivation in squamous cell carcinoma of the head and neck (SCCHN) by multiple molecular mechanisms. Oral Oncol 41(10):1013–1020PubMedCrossRefPubMedCentralGoogle Scholar
  15. Bonner WM, Redon CE, Dickey JS, Nakamura AJ, Sedelnikova OA, Solier S, Pommier Y (2008) GammaH2AX and cancer. Nat Rev Cancer 8(12):957–967PubMedPubMedCentralCrossRefGoogle Scholar
  16. Bristow RG, Hill RP (2008) Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8(3):180–192PubMedCrossRefPubMedCentralGoogle Scholar
  17. Brown EJ, Baltimore D (2000) ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev 14(4):397–402PubMedPubMedCentralGoogle Scholar
  18. Bueno RC, Canevari RA, Villacis RA, Domingues MA, Caldeira JR, Rocha RM, Drigo SA, Rogatto SR (2014) ATM down-regulation is associated with poor prognosis in sporadic breast carcinomas. Ann Oncol 25(1):69–75PubMedCrossRefPubMedCentralGoogle Scholar
  19. Byrd JC, Gribben JG, Peterson BL, Grever MR, Lozanski G, Lucas DM, Lampson B, Larson RA, Caligiuri MA, Heerema NA (2006) Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol 24(3):437–443PubMedCrossRefPubMedCentralGoogle Scholar
  20. Caldecott KW (2003) XRCC1 and DNA strand break repair. DNA Repair 2(9):955–969PubMedPubMedCentralCrossRefGoogle Scholar
  21. Camidge DR, Randall KR, Foster JR, Sadler CJ, Wright JA, Soames AR, Laud PJ, Smith PD, Hughes AM (2005) Plucked human hair as a tissue in which to assess pharmacodynamic end points during drug development studies. Br J Cancer 92(10):1837–1841PubMedPubMedCentralCrossRefGoogle Scholar
  22. 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
  23. Chan N, Pires IM, Bencokova Z, Coackley C, Luoto KR, Bhogal N, Lakshman M, Gottipati P, Oliver FJ, Helleday T, Hammond EM, Bristow RG (2010) Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. Cancer Res 70(20):8045–8054PubMedPubMedCentralCrossRefGoogle Scholar
  24. Chanan-Khan A, Holkova B, Perle M, Reich E, Wu C, Inghirami G, Takeshita K (2003) T-cell clonality and myelodysplasia without chromosomal fragility in a patient with features of Seckel syndrome. Haematologica 88(5):ECR14PubMedPubMedCentralGoogle Scholar
  25. Chanoux RA, Yin B, Urtishak KA, Asare A, Bassing CH, Brown EJ (2009) ATR and H2AX cooperate in maintaining genome stability under replication stress. J Biol Chem 284(9):5994–6003PubMedPubMedCentralCrossRefGoogle Scholar
  26. 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(7):2320–2330PubMedPubMedCentralCrossRefGoogle Scholar
  27. Chen T, Middleton FK, Falcon S, Reaper PM, Pollard JR, Curtin NJ (2015) Development of pharmacodynamic biomarkers for ATR inhibitors. Mol Oncol 9(2):463–472PubMedCrossRefPubMedCentralGoogle Scholar
  28. Chen T, Stephens PA, Middleton FK, Curtin NJ (2012) Targeting the S and G2 checkpoint to treat cancer. Drug Discov Today 17(5-6):194–202PubMedCrossRefPubMedCentralGoogle Scholar
  29. Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40(2):179–204PubMedPubMedCentralCrossRefGoogle Scholar
  30. Cimprich KA, Cortez D (2008) ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9(8):616–627PubMedPubMedCentralCrossRefGoogle Scholar
  31. 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):1599–1606PubMedPubMedCentralCrossRefGoogle Scholar
  32. 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
  33. d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426(6963):194–198PubMedCrossRefPubMedCentralGoogle Scholar
  34. 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
  35. Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C, Schurra C, Garre M, Nuciforo PG, Bensimon A, Maestro R, Pelicci PG, d’Adda di Fagagna F (2006) Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444(7119):638–642PubMedPubMedCentralCrossRefGoogle Scholar
  36. Dillon M, Ellis S, Grove L, McLellan L, Clack G, Smith DS, Laude J, Viney Z, Adeleke S, Lazaridis G, Spicer JF, Forster MD, Harrington KJ (2016) PATRIOT: a phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy in patients with solid tumours. ASCO Meet Abstr 34(15_suppl):TPS2603Google Scholar
  37. Dillon MT, Barker HE, Pedersen M, Hafsi H, Bhide SA, Newbold KL, Nutting CM, McLaughlin M, Harrington KJ (2017a) Radiosensitization by the ATR Inhibitor AZD6738 through Generation of Acentric Micronuclei. Mol Cancer Ther 16(1):25–34PubMedCrossRefGoogle Scholar
  38. Dillon MT, Espinasse A, Ellis S, Mohammed K, Grove L, McLellan L, Smith SA, Ross G, Woo K, Adeleke S, Josephides E, Spicer J, Forster MD, Harrington KJ (2017b) A phase I multicenter dose-escalation study of AZD6738 ATR inhibitor monotherapy in advanced solid tumors (PATRIOT Part A): preliminary results. AACR Annual Meeting, Washington, DCGoogle Scholar
  39. Dillon MT, Good JS, Harrington KJ (2014) Selective targeting of the G2/M cell cycle checkpoint to improve the therapeutic index of radiotherapy. Clin Oncol (R Coll Radiol) 26(5):257–265CrossRefGoogle Scholar
  40. Dillon MT, Harrington KJ (2015) Human Papillomavirus-Negative Pharyngeal Cancer. J Clin Oncol 33(29):3251–3261PubMedCrossRefPubMedCentralGoogle Scholar
  41. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455(7216):1069–1075PubMedPubMedCentralCrossRefGoogle Scholar
  42. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343(26):1910–1916PubMedCrossRefPubMedCentralGoogle Scholar
  43. Dohner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M, Fischer K, Hunstein W, Lichter P (1997) 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood 89(7):2516–2522PubMedPubMedCentralGoogle Scholar
  44. Fang Y, Tsao CC, Goodman BK, Furumai R, Tirado CA, Abraham RT, Wang XF (2004) ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background. EMBO J 23(15):3164–3174PubMedPubMedCentralCrossRefGoogle Scholar
  45. 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):14349–14355PubMedPubMedCentralCrossRefGoogle Scholar
  46. Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, Bersani F, Pineda JR, Suva ML, Benes CH, Haber DA, Boussin FD, Zou L (2015) Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 347(6219):273–277PubMedPubMedCentralCrossRefGoogle Scholar
  47. Fokas E, Prevo R, Pollard JR, Reaper PM, Charlton PA, Cornelissen B, Vallis KA, Hammond EM, Olcina MM, Gillies W, McKenna RJM, 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
  48. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123–134PubMedPubMedCentralCrossRefGoogle Scholar
  49. 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-y l}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity. J Med Chem 56(5):2125–2138PubMedPubMedCentralCrossRefGoogle Scholar
  50. Foote KM, Lau A, JW MN (2015) Drugging ATR: progress in the development of specific inhibitors for the treatment of cancer. Future Med Chem 7(7):873–891PubMedPubMedCentralCrossRefGoogle Scholar
  51. Fracasso PM, Williams KJ, Chen RC, Picus J, Ma CX, Ellis MJ, Tan BR, Pluard TJ, Adkins DR, Naughton MJ, Rader JS, Arquette MA, Fleshman JW, Creekmore AN, Goodner SA, Wright LP, Guo Z, Ryan CE, Tao Y, Soares EM, Cai S-r, Lin L, Dancey J, Rudek MA, McLeod HL, Piwnica-Worms H (2011) A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies. Cancer Chemother Pharmacol 67(6):1225–1237PubMedCrossRefPubMedCentralGoogle Scholar
  52. Gaillard H, Garcia-Muse T, Aguilera A (2015) Replication stress and cancer. Nat Rev Cancer 15(5):276–289PubMedPubMedCentralCrossRefGoogle Scholar
  53. Gamper AM, Rofougaran R, Watkins SC, Greenberger JS, Beumer JH, Bakkenist CJ (2013) ATR kinase activation in G1 phase facilitates the repair of ionizing radiation-induced DNA damage. Nucleic Acids Res 41(22):10334–10344PubMedPubMedCentralCrossRefGoogle Scholar
  54. 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
  55. Guarini A, Marinelli M, Tavolaro S, Bellacchio E, Magliozzi M, Chiaretti S, De Propris MS, Peragine N, Santangelo S, Paoloni F, Nanni M, Del Giudice I, Mauro FR, Torrente I, Foà R (2012) ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression. Haematologica 97(1):47–55PubMedPubMedCentralCrossRefGoogle Scholar
  56. Guichard SM, Brown E, Odedra R, Hughes A, Heathcote D, Barnes J, Lau A, Powell S, Jones CD, Nissink W, Foote KM, Jewsbury PJ, Pass M (2013) Abstract 3343: the pre-clinical in vitro and in vivo activity of AZD6738: a potent and selective inhibitor of ATR kinase. Cancer Res 73(8 Supplement):3343CrossRefGoogle Scholar
  57. Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319(5868):1352–1355PubMedPubMedCentralCrossRefGoogle Scholar
  58. 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 J-D, 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(14):5674–5685PubMedPubMedCentralCrossRefGoogle Scholar
  59. Hammond EM, Denko NC, Dorie MJ, Abraham RT, Giaccia AJ (2002) Hypoxia links ATR and p53 through replication arrest. Mol Cell Biol 22(6):1834–1843PubMedPubMedCentralCrossRefGoogle Scholar
  60. Hammond EM, Dorie MJ, Giaccia AJ (2003) ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. J Biol Chem 278(14):12207–12213PubMedPubMedCentralCrossRefGoogle Scholar
  61. Hammond EM, Dorie MJ, Giaccia AJ (2004) Inhibition of ATR leads to increased sensitivity to hypoxia/reoxygenation. Cancer Res 64(18):6556–6562PubMedPubMedCentralCrossRefGoogle Scholar
  62. Hammond EM, Kaufmann MR, Giaccia AJ (2007) Oxygen sensing and the DNA-damage response. Curr Opin Cell Biol 19(6):680–684PubMedCrossRefPubMedCentralGoogle Scholar
  63. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674PubMedPubMedCentralCrossRefGoogle Scholar
  64. Harrington KJ, Billingham LJ, Brunner TB, Burnet NG, Chan CS, Hoskin P, Mackay RI, Maughan TS, Macdougall J, McKenna WG, Nutting CM, Oliver A, Plummer R, Stratford IJ, Illidge T (2011) Guidelines for preclinical and early phase clinical assessment of novel radiosensitisers. Br J Cancer 105(5):628–639PubMedPubMedCentralCrossRefGoogle Scholar
  65. Hayani A, Suarez CR, Molnar Z, LeBeau M, Godwin J (1994) Acute myeloid leukaemia in a patient with Seckel syndrome. J Med Genet 31(2):148–149PubMedPubMedCentralCrossRefGoogle Scholar
  66. Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S, Offerhaus GJ, McLendon R, Rasheed BA, He Y, Yan H, Bigner DD, Oba-Shinjo SM, Marie SKN, Riggins GJ, Kinzler KW, Vogelstein B, Hruban RH, Maitra A, Papadopoulos N, Meeker AK (2011) Altered telomeres in tumors with ATRX and DAXX mutations. Science 333(6041):425PubMedPubMedCentralCrossRefGoogle Scholar
  67. Hu H, Du L, Nagabayashi G, Seeger RC, Gatti RA (2010) ATM is down-regulated by N-Myc-regulated microRNA-421. Proc Natl Acad Sci U S A 107(4):1506–1511PubMedPubMedCentralCrossRefGoogle Scholar
  68. 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
  69. Jacq X, Smith L, Brown E, Hughes A, Odedra R, Heathcote D, Barnes J, Powell S, Maguire S, Pearson V, Boros J, Caie P, Thommes PA, Nissink W, Foote K, Jewsbury PJ, Guichard SM (2012) Abstract 1823: AZ20, a novel potent and selective inhibitor of ATR kinase with in vivo antitumour activity. Cancer Res 72(8 Supplement):1823CrossRefGoogle Scholar
  70. Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP (2006) ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol 8(1):37–45PubMedCrossRefGoogle Scholar
  71. 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 (2013a) Abstract 2348: discovery of AZD6738, a potent and selective inhibitor with the potential to test the clinical efficacy of ATR kinase inhibition in cancer patients. Cancer Res 73(8 Supplement):2348CrossRefGoogle Scholar
  72. Jones RM, Mortusewicz O, Afzal I, Lorvellec M, Garcia P, Helleday T, Petermann E (2013b) Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress. Oncogene 32(32):3744–3753PubMedPubMedCentralCrossRefGoogle Scholar
  73. Josse 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
  74. Kim ST, Lim DS, Canman CE, Kastan MB (1999) Substrate specificities and identification of putative substrates of ATM kinase family members. J Biol Chem 274(53):37538–37543PubMedCrossRefPubMedCentralGoogle Scholar
  75. Kirschner K, Melton DW (2010) Multiple roles of the ERCC1-XPF endonuclease in DNA repair and resistance to anticancer drugs. Anticancer Res 30(9):3223–3232PubMedPubMedCentralGoogle Scholar
  76. Kotov IN, Siebring-van Olst E, Knobel PA, van der Meulen-Muileman IH, Felley-Bosco E, van Beusechem VW, Smit EF, Stahel RA, Marti TM (2014) Whole genome RNAi screens reveal a critical role of REV3 in coping with replication stress. Mol Oncol 8(8):1747–1759PubMedPubMedCentralCrossRefGoogle Scholar
  77. 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):3474PubMedPubMedCentralCrossRefGoogle Scholar
  78. 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):582–595PubMedPubMedCentralCrossRefGoogle Scholar
  79. Lavin MF, Scott S, Gueven N, Kozlov S, Peng C, Chen P (2004) Functional consequences of sequence alterations in the ATM gene. DNA Repair 3(8–9):1197–1205PubMedPubMedCentralCrossRefGoogle Scholar
  80. Lecona E, Fernandez-Capetillo O (2014) Replication stress and cancer: it takes two to tango. Exp Cell Res 329(1):26–34PubMedPubMedCentralCrossRefGoogle Scholar
  81. Lee HE, Han N, Kim MA, Lee HS, Yang HK, Lee BL, Kim WH (2014) DNA damage response-related proteins in gastric cancer: ATM, Chk2 and p53 expression and their prognostic value. Pathobiology 81(1):25–35PubMedCrossRefPubMedCentralGoogle Scholar
  82. Lewis KA, Lilly KK, Reynolds EA, Sullivan WP, Kaufmann SH, Cliby WA (2009) Ataxia telangiectasia and rad3-related kinase contributes to cell cycle arrest and survival after cisplatin but not oxaliplatin. Mol Cancer Ther 8(4):855–863PubMedPubMedCentralCrossRefGoogle Scholar
  83. Lim AM, Young RJ, Collins M, Fox SB, McArthur GA, Corry J, Peters L, Rischin D, Solomon B (2012) Correlation of Ataxia-Telangiectasia-Mutated (ATM) gene loss with outcome in head and neck squamous cell carcinoma. Oral Oncol 48(8):698–702PubMedCrossRefPubMedCentralGoogle Scholar
  84. Lopez-Contreras AJ, Fernandez-Capetillo O (2010) The ATR barrier to replication-born DNA damage. DNA Repair (Amst) 9(12):1249–1255CrossRefGoogle Scholar
  85. López-Contreras AJ, Gutierrez-Martinez P, Specks J, Rodrigo-Perez S, Fernandez-Capetillo O (2012) An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation. J Exp Med 209(3):455–461PubMedPubMedCentralCrossRefGoogle Scholar
  86. Lovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J, de Lange T, De S, Petrini JHJ, Sung PA, Jasin M, Rosenbluh J, Zwang Y, Weir BA, Hatton C, Ivanova E, Macconaill L, Hanna M, Hahn WC, Lue NF, Reddel RR, Jiao Y, Kinzler K, Vogelstein B, Papadopoulos N, Meeker AK, ALT Starr Cancer Consortium (2012) Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet 8(7):e1002772PubMedPubMedCentralCrossRefGoogle Scholar
  87. Manda G, Isvoranu G, Comanescu MV, Manea A, Debelec Butuner B, Korkmaz KS (2015) The redox biology network in cancer pathophysiology and therapeutics. Redox Biol 5:347–357PubMedPubMedCentralCrossRefGoogle Scholar
  88. McNees CJ, Tejera AM, Martínez P, Murga M, Mulero F, Fernandez-Capetillo O, Blasco MA (2010) ATR suppresses telomere fragility and recombination but is dispensable for elongation of short telomeres by telomerase. J Cell Biol 188(5):639–652PubMedPubMedCentralCrossRefGoogle Scholar
  89. Middleton FK, Patterson MJ, Elstob CJ, Fordham S, Herriott A, Wade MA, McCormick A, Edmondson R, May FE, Allan JM, Pollard JR, Curtin NJ (2015) Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition. Oncotarget 6(32):32396–32409PubMedPubMedCentralCrossRefGoogle Scholar
  90. Min A, Im SA, Jang H, Kim S, Lee M, Kim DK, Yang Y, Kim HJ, Lee KH, Kim JW, Kim TY, Oh DY, Brown J, Lau A, O’Connor MJ, Bang YJ (2017) AZD6738, a novel oral inhibitor of ATR, induces synthetic lethality with ATM deficiency in gastric cancer cells. Mol Cancer Ther 16(4):566–577PubMedCrossRefPubMedCentralGoogle Scholar
  91. Mohni KN, Kavanaugh GM, Cortez D (2014) ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency. Cancer Res 74(10):2835–2845PubMedPubMedCentralCrossRefGoogle Scholar
  92. Mohni KN, Thompson PS, Luzwick JW, Glick GG, Pendleton CS, Lehmann BD, Pietenpol JA, Cortez D (2015) A synthetic lethal screen identifies DNA repair pathways that sensitize cancer cells to combined ATR inhibition and cisplatin treatments. PLoS One 10(5):e0125482PubMedPubMedCentralCrossRefGoogle Scholar
  93. Morrison C, Sonoda E, Takao N, Shinohara A, Yamamoto K, Takeda S (2000) The controlling role of ATM in homologous recombinational repair of DNA damage. EMBO J 19(3):463–471PubMedPubMedCentralCrossRefGoogle Scholar
  94. Murga M, Bunting S, Montana MF, Soria R, Mulero F, Canamero M, Lee Y, McKinnon PJ, Nussenzweig A, Fernandez-Capetillo O (2009) A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging. Nat Genet 41(8):891–898PubMedPubMedCentralCrossRefGoogle Scholar
  95. Murga M, Campaner S, Lopez-Contreras AJ, Toledo LI, Soria R, Montana 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
  96. Nam EA, Zhao R, Glick GG, Bansbach CE, Friedman DB, Cortez D (2011) Thr-1989 phosphorylation is a marker of active ataxia telangiectasia-mutated and Rad3-related (ATR) kinase. J Biol Chem 286(33):28707–28714PubMedPubMedCentralCrossRefGoogle Scholar
  97. Nghiem P, Park PK, Kim Y, 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
  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’Carrigan B, de Miguel Luken MJ, Papadatos-Pastos D, Brown J, Tunariu N, Perez Lopez R, Ganegoda M, Riisnaes R, Figueiredo I, Carreira S, Hare B, Yang F, McDermott K, Penney MS, Pollard J, Lopez JS, Banerji U, De Bono JS, Fields SZ, Yap TA (2016) Phase I trial of a first-in-class ATR inhibitor VX-970 as monotherapy (mono) or in combination (combo) with carboplatin (CP) incorporating pharmacodynamics (PD) studies. ASCO Meet Abstr 34(15_suppl):2504Google 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. Olcina M, Lecane PS, Hammond EM (2010) Targeting hypoxic cells through the DNA damage response. Clin Cancer Res 16(23):5624–5629PubMedPubMedCentralCrossRefGoogle Scholar
  102. Olive PL (2011) Retention of gammaH2AX foci as an indication of lethal DNA damage. Radiother Oncol 101(1):18–23PubMedCrossRefPubMedCentralGoogle Scholar
  103. Ouillette P, Fossum S, Parkin B, Ding L, Bockenstedt P, Al-Zoubi A, Shedden K, Malek SN (2010) Aggressive chronic lymphocytic leukemia with elevated genomic complexity is associated with multiple gene defects in the response to DNA double-strand breaks. Clin Cancer Res 16(3):835–847PubMedPubMedCentralCrossRefGoogle Scholar
  104. Park JS, Na HJ, Pyo JH, Jeon HJ, Kim YS, Yoo MA (2015) Requirement of ATR for maintenance of intestinal stem cells in aging Drosophila. Aging (Albany N Y) 7(5):307–318Google Scholar
  105. 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
  106. Pennarun G, Hoffschir F, Revaud D, Granotier C, Gauthier LR, Mailliet P, Biard DS, Boussin FD (2010) ATR contributes to telomere maintenance in human cells. Nucleic Acids Res 38(9):2955–2963PubMedPubMedCentralCrossRefGoogle Scholar
  107. Perez RP, Lewis LD, Beelen AP, Olszanski AJ, Johnston N, Rhodes CH, Beaulieu B, Ernstoff MS, Eastman A (2006) Modulation of cell cycle progression in human tumors: a pharmacokinetic and tumor molecular pharmacodynamic study of cisplatin plus the Chk1 inhibitor UCN-01 (NSC 638850). Clin Cancer Res 12(23):7079–7085PubMedCrossRefPubMedCentralGoogle Scholar
  108. Pires IM, Bencokova Z, Milani M, Folkes LK, Li JL, Stratford MR, Harris AL, Hammond EM (2010) Effects of acute versus chronic hypoxia on DNA damage responses and genomic instability. Cancer Res 70(3):925–935PubMedPubMedCentralCrossRefGoogle Scholar
  109. 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
  110. Plummer ER, Dean EJ, Evans TRJ, Greystoke A, Herbschleb K, Ranson M, Brown J, Zhang Y, Karan S, Pollard J, Penney MS, Asmal M, Fields SZ, Middleton MR (2016) Phase I trial of first-in-class ATR inhibitor VX-970 in combination with gemcitabine (Gem) in advanced solid tumors (NCT02157792). J Clin Oncol 34(suppl):abstr 2513CrossRefGoogle Scholar
  111. Powell SN, DeFrank JS, Connell P, Eogan M, Preffer F, Dombkowski D, Tang W, Friend S (1995) Differential sensitivity of p53(-) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. Cancer Res 55(8):1643–1648PubMedPubMedCentralGoogle Scholar
  112. 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
  113. 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):428–430PubMedPubMedCentralCrossRefGoogle Scholar
  114. Rossi D, Gaidano G (2012) ATM and chronic lymphocytic leukemia: mutations, and not only deletions, matter. Haematologica 97(1):5PubMedPubMedCentralCrossRefGoogle Scholar
  115. Ruzankina Y, Schoppy DW, Asare A, Clark CE, Vonderheide RH, Brown EJ (2009) Tissue regenerative delays and synthetic lethality in adult mice after combined deletion of Atr and Trp53. Nat Genet 41(10):1144–1149PubMedPubMedCentralCrossRefGoogle Scholar
  116. Sanjiv K, Hagenkort A, José M, Calderón-Montaño TK, Philip M, Reaper OM, Sylvain A, Jacques RV, Kuiper NS, Scobie M, Peter A, Charlton JR, Pollard UW, Berglund MA, Helleday T (2016) Cancer-specific synthetic lethality between ATR and CHK1 kinase activities. Cell Rep 14(2):298–309PubMedPubMedCentralCrossRefGoogle Scholar
  117. 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
  118. Scanlon SE, Glazer PM (2015) Multifaceted control of DNA repair pathways by the hypoxic tumor microenvironment. DNA Repair (Amst) 32:180CrossRefGoogle Scholar
  119. Schaffner C, Stilgenbauer S, Rappold GA, Döhner H, Lichter P (1999) Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia. Blood 94:748PubMedPubMedCentralGoogle Scholar
  120. Shiloh Y (2003) ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3(3):155–168PubMedPubMedCentralCrossRefGoogle Scholar
  121. 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
  122. Skowronska A, Parker A, Ahmed G, Oldreive C, Davis Z, Richards S, Dyer M, Matutes E, Gonzalez D, Taylor AM, Moss P, Thomas P, Oscier D, Stankovic T (2012) Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial. J Clin Oncol 30(36):4524–4532PubMedCrossRefPubMedCentralGoogle Scholar
  123. Stankovic T, Stewart GS, Fegan C, Biggs P, Last J, Byrd PJ, Keenan RD, Moss PAH, Taylor AMR (2002) Ataxia telangiectasia mutated–deficient B-cell chronic lymphocytic leukemia occurs in pregerminal center cells and results in defective damage response and unrepaired chromosome damage. Blood 99(1):300PubMedCrossRefPubMedCentralGoogle Scholar
  124. Stankovic T, Weber P, Stewart G, Bedenham T, Murray J, Byrd PJ, Moss PA, Taylor AM (1999) Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet 353(9146):26–29PubMedCrossRefPubMedCentralGoogle Scholar
  125. Stokes MP, Rush J, Macneill J, Ren JM, Sprott K, Nardone J, Yang V, Beausoleil SA, Gygi SP, Livingstone M, Zhang H, Polakiewicz RD, Comb MJ (2007) Profiling of UV-induced ATM/ATR signaling pathways. Proc Natl Acad Sci U S A 104(50):19855–19860PubMedPubMedCentralCrossRefGoogle 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. Tanaka T, Halicka HD, Huang X, Traganos F, Darzynkiewicz Z (2006) Constitutive histone H2AX phosphorylation and ATM activation, the reporters of DNA damage by endogenous oxidants. Cell Cycle 5(17):1940–1945PubMedPubMedCentralCrossRefGoogle Scholar
  128. Thanasoula M, Escandell JM, Suwaki N, Tarsounas M (2012) ATM/ATR checkpoint activation downregulates CDC25C to prevent mitotic entry with uncapped telomeres. EMBO J 31(16):3398–3410PubMedPubMedCentralCrossRefGoogle Scholar
  129. Toledo LI, Murga M, Fernandez-Capetillo O (2011a) Targeting ATR and Chk1 kinases for cancer treatment: a new model for new (and old) drugs. Mol Oncol 5(4):368–373PubMedPubMedCentralCrossRefGoogle Scholar
  130. Toledo LI, Murga M, Gutierrez-Martinez P, Soria R, Fernandez-Capetillo O (2008) ATR signaling can drive cells into senescence in the absence of DNA breaks. Genes Dev 22(3):297–302PubMedPubMedCentralCrossRefGoogle Scholar
  131. Toledo LI, Murga M, Zur R, Soria R, Rodriguez A, Martinez S, Oyarzabal J, Pastor J, Bischoff JR, Fernandez-Capetillo O (2011b) 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. 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
  133. Wagner JM, Karnitz LM (2009) Cisplatin-induced DNA damage activates replication checkpoint signaling components that differentially affect tumor cell survival. Mol Pharmacol 76(1):208–214PubMedPubMedCentralCrossRefGoogle Scholar
  134. Walsh CS (2015) Two decades beyond BRCA1/2: homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy. Gynecol Oncol 137(2):343–350PubMedCrossRefPubMedCentralGoogle Scholar
  135. Wang W (2007) Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet 8(10):735–748PubMedCrossRefPubMedCentralGoogle Scholar
  136. Watkins JA, Irshad S, Grigoriadis A, Tutt AN (2014) Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res 16(3):211PubMedPubMedCentralCrossRefGoogle Scholar
  137. Weber AM, Bokobza SM, Devery AM, Ryan AJ (2013) Abstract B91: combined ATM and ATR kinase inhibition selectively kills p53-mutated non-small cell lung cancer (NSCLC) cells. Mol Cancer Ther 12(11 Supplement):B91CrossRefGoogle Scholar
  138. 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):1406–1413PubMedPubMedCentralCrossRefGoogle Scholar
  139. Yap TA, Lorente D, Omlin A, Olmos D, de Bono JS (2014) Circulating tumor cells: a multifunctional biomarker. Clin Cancer Res 20(10):2553–2568PubMedCrossRefPubMedCentralGoogle Scholar
  140. Zeman MK, Cimprich KA (2014) Causes and consequences of replication stress. Nat Cell Biol 16(1):2–9PubMedPubMedCentralCrossRefGoogle Scholar
  141. Zhang C, Yan Z, Painter CL, Zhang Q, Chen E, Arango ME, Kuszpit K, Zasadny K, Hallin M, Hallin J, Wong A, Buckman D, Sun G, Qiu M, Anderes K, Christensen JG (2009) PF-00477736 mediates checkpoint kinase 1 signaling pathway and potentiates docetaxel-induced efficacy in xenografts. Clin Cancer Res 15(14):4630–4640PubMedCrossRefGoogle Scholar
  142. 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

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Magnus T. Dillon
    • 1
    • 2
  • Kevin J. Harrington
    • 1
    • 2
  1. 1.The Institute of Cancer ResearchLondonUK
  2. 2.The Royal Marsden NHS Foundation TrustLondonUK

Personalised recommendations