{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:27:58Z","timestamp":1790857678782,"version":"4.1.0"},"reference-count":147,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2017,4,27]],"date-time":"2017-04-27T00:00:00Z","timestamp":1493251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Targeting the DNA damage response (DDR) is a new therapeutic approach in cancer that shows great promise for tumour selectivity. Key components of the DDR are the ataxia telangiectasia mutated and Rad3 related (ATR) and checkpoint kinase 1 (CHK1) kinases. This review article describes the role of ATR and its major downstream target, CHK1, in the DDR and why cancer cells are particularly reliant on the ATR-CHK1 pathway, providing the rationale for targeting these kinases, and validation of this hypothesis by genetic manipulation. The recent development of specific inhibitors and preclinical data using these inhibitors not only as chemosensitisers and radiosensitisers but also as single agents to exploit specific pathologies of tumour cells is described. These potent and specific inhibitors have now entered clinical trial and early results are presented.<\/jats:p>","DOI":"10.3390\/cancers9050041","type":"journal-article","created":{"date-parts":[[2017,4,27]],"date-time":"2017-04-27T13:01:15Z","timestamp":1493298075000},"page":"41","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":208,"title":["Targeting the ATR-CHK1 Axis in Cancer Therapy"],"prefix":"10.3390","volume":"9","author":[{"given":"Stuart","family":"Rundle","sequence":"first","affiliation":[{"name":"Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Bradbury","sequence":"additional","affiliation":[{"name":"Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvette","family":"Drew","sequence":"additional","affiliation":[{"name":"Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Curtin","sequence":"additional","affiliation":[{"name":"Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1038\/nrc3399","article-title":"DNA repair dysregulation from cancer driver to therapeutic target","volume":"12","author":"Curtin","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s40265-016-0688-7","article-title":"PARP Inhibitors in Reproductive System Cancers: Current Use and Developments","volume":"77","author":"Chen","year":"2017","journal-title":"Drugs"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/nature03094","article-title":"G1 cell-cycle control and cancer","volume":"432","author":"Massague","year":"2004","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1101\/gad.14.12.1439","article-title":"Aberrant cell cycle checkpoint function and early embryonic death in Chk1(\u2212\/\u2212) mice","volume":"14","author":"Takai","year":"2000","journal-title":"Genes Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1101\/gad.14.4.397","article-title":"ATR disruption leads to chromosomal fragmentation and early embryonic lethality","volume":"14","author":"Brown","year":"2000","journal-title":"Genes Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/emboj\/17.1.159","article-title":"Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints","volume":"17","author":"Cliby","year":"1998","journal-title":"EMBO J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/ncb2897","article-title":"Causes and consequences of replication stress","volume":"16","author":"Zeman","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/nrm2450","article-title":"ATR: An essential regulator of genome integrity","volume":"9","author":"Cimprich","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1101\/gad.1522607","article-title":"The structural determinants of checkpoint activation","volume":"21","author":"MacDougall","year":"2007","journal-title":"Genes Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"a012716","DOI":"10.1101\/cshperspect.a012716","article-title":"DNA Damage Sensing by the ATM and ATR Kinases","volume":"5","author":"Zou","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13660","DOI":"10.1073\/pnas.1007856107","article-title":"Reconstitution of RPA-covered single-stranded DNA-activated ATR-Chk1 signaling","volume":"107","author":"Choi","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1126\/science.1065521","article-title":"ATR and ATRIP: Partners in checkpoint signaling","volume":"294","author":"Cortez","year":"2001","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3367","DOI":"10.1128\/MCB.02238-06","article-title":"Function of a conserved checkpoint recruitment domain in ATRIP proteins","volume":"27","author":"Ball","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1242\/jcs.035105","article-title":"ATR signaling at a glance","volume":"122","author":"Shiotani","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1126\/science.271.5247.353","article-title":"Rad-dependent response of the CHK1-encoded protein kinase at the DNA damage checkpoint","volume":"271","author":"Walworth","year":"1996","journal-title":"Science"},{"key":"ref_17","first-page":"A1582","article-title":"DNA damage checkpoint signaling through the protein kinase Chk1","volume":"14","author":"Walworth","year":"2000","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1101\/gad.14.12.1448","article-title":"Chk1 is an essential kinase that is regulated by Atr and required for the G(2)\/M DNA damage checkpoint","volume":"14","author":"Liu","year":"2000","journal-title":"Genes Dev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6056","DOI":"10.1128\/MCB.00492-06","article-title":"Claspin operates downstream of TopBP1 to direct ATR signaling towards Chk1 activation","volume":"26","author":"Liu","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S1097-2765(05)00092-4","article-title":"Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts","volume":"6","author":"Kumagai","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.molcel.2006.06.022","article-title":"Rad17 phosphorylation is required for claspin recruitment and Chk1 activation in response to replication stress","volume":"23","author":"Wang","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3681","DOI":"10.1111\/febs.13387","article-title":"DNA damage control: Regulation and functions of checkpoint kinase 1","volume":"282","author":"Smits","year":"2015","journal-title":"FEBS J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1093\/nar\/gkr697","article-title":"Safeguarding genome integrity: The checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication","volume":"40","author":"Sorensen","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7488","DOI":"10.1128\/MCB.23.21.7488-7497.2003","article-title":"Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14\u20133-3 binding","volume":"23","author":"Chen","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1158\/1078-0432.CCR-09-1029","article-title":"New Insights into Checkpoint Kinase 1 in the DNA Damage Response Signaling Network","volume":"16","author":"Dai","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1091\/mbc.12.3.551","article-title":"Positive regulation of Wee1 by Chk1 and 14-3-3 proteins","volume":"12","author":"Lee","year":"2001","journal-title":"Mol. Biol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1042\/BJ20102162","article-title":"AIR signalling: More than meeting at the fork","volume":"436","author":"Nam","year":"2011","journal-title":"Biochem. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S1535-6108(03)00048-5","article-title":"Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A","volume":"3","author":"Sorensen","year":"2003","journal-title":"Cancer Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.dnarep.2007.02.015","article-title":"The ATR pathway: Fine-tuning the fork","volume":"6","author":"Paulsen","year":"2007","journal-title":"DNA Repair"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1158\/0008-5472.CAN-11-2904","article-title":"ATR-ATRIP Kinase Complex Triggers Activation of the Fanconi Anemia DNA Repair Pathway","volume":"72","author":"Shigechi","year":"2012","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1101\/gad.1196104","article-title":"ATR couples FANCD2 monoubiquitination to the DNA-damage response","volume":"18","author":"Andreassen","year":"2004","journal-title":"Genes Dev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/sj.onc.1209828","article-title":"ATR-dependent checkpoint modulates XPA nuclear import in response to UV irradiation","volume":"26","author":"Wu","year":"2007","journal-title":"Oncogene"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1101\/gad.851000","article-title":"Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress","volume":"14","author":"Tibbetts","year":"2000","journal-title":"Genes Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/ncb1212","article-title":"The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair","volume":"7","author":"Sorensen","year":"2005","journal-title":"Nat. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/bjc.2011.243","article-title":"Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines","volume":"105","author":"Peasland","year":"2011","journal-title":"Br. J. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1158\/1535-7163.MCT-08-0662","article-title":"Gemcitabine sensitization by checkpoint kinase 1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells","volume":"8","author":"Parsels","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4972","DOI":"10.1158\/0008-5472.CAN-09-3573","article-title":"Mechanism of radiosensitization by the Chk1\/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair","volume":"70","author":"Morgan","year":"2010","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1073\/pnas.92.6.2298","article-title":"Nuclear foci of mammalian Rad51 recombination protein in somatic cells after DNA damage and its localization in synaptonemal complexes","volume":"92","author":"Haaf","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.molcel.2016.12.007","article-title":"Coupling of Homologous Recombination and the Checkpoint by ATR","volume":"65","author":"Buisson","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","article-title":"The Hallmarks of Cancer","volume":"100","author":"Hanahan","year":"2000","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/0092-8674(92)90586-2","article-title":"Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells","volume":"71","author":"Hartwell","year":"1992","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1126\/science.274.5293.1672","article-title":"Cancer Cell Cycles","volume":"274","author":"Sherr","year":"1996","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1056\/NEJMra072367","article-title":"Oncogenes and Cancer","volume":"358","author":"Croce","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1126\/science.1140735","article-title":"An Oncogene-Induced DNA Damage Model for Cancer Development","volume":"319","author":"Halazonetis","year":"2008","journal-title":"Science"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/ng1129","article-title":"A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome","volume":"33","author":"Woods","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1074\/jbc.M106287200","article-title":"S Phase and G2 Arrests Induced by Topoisomerase I Poisons Are Dependent on ATR Kinase Function","volume":"277","author":"Cliby","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"9092","DOI":"10.1073\/pnas.161281798","article-title":"ATR inhibition selectively sensitizes G(1) checkpoint-deficient cells to lethal premature chromatin condensation","volume":"98","author":"Nghiem","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.4161\/cc.3.9.1080","article-title":"Chk1, but not Chk2, is Involved in the Cellular Response to DNA Damaging Agents: Differential Activity in Cells Expressing, or not, p53","volume":"3","author":"Carrassa","year":"2004","journal-title":"Cell Cycle"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"14349","DOI":"10.1074\/jbc.M411890200","article-title":"The Role of Checkpoint Kinase 1 in Sensitivity to Topoisomerase I Poisons","volume":"280","author":"Flatten","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5131","DOI":"10.1158\/1078-0432.CCR-08-0304","article-title":"Checkpoint Kinase 1 Down-Regulation by an Inducible Small Interfering RNA Expression System Sensitized in vivo Tumors to Treatment with 5-Fluorouracil","volume":"14","author":"Ganzinelli","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.4161\/cbt.8.16.8955","article-title":"Knockdown of Chk1 sensitizes human colon carcinoma HCT116 cells in a p53-dependent manner to lidamycin through abrogation of a G2\/M checkpoint and induction of apoptosis","volume":"8","author":"Pan","year":"2009","journal-title":"Cancer Biol. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1479-5876-7-43","article-title":"Synthetic lethal RNAi screening identifies sensitizing targets for gemcitabine therapy in pancreatic cancer","volume":"7","author":"Azorsa","year":"2009","journal-title":"J. Transl. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1124\/mol.109.055178","article-title":"Cisplatin-Induced DNA Damage Activates Replication Checkpoint Signaling Components that Differentially Affect Tumor Cell Survival","volume":"76","author":"Wagner","year":"2009","journal-title":"Mol. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6149","DOI":"10.1038\/onc.2010.343","article-title":"Status of p53 in human cancer cells does not predict efficacy of CHK1 kinase inhibitors combined with chemotherapeutic agents","volume":"29","author":"Zenvirt","year":"2010","journal-title":"Oncogene"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6600","DOI":"10.1038\/sj.onc.1204085","article-title":"Small molecule modulators of cyclin-dependent kinases for cancer therapy","volume":"19","author":"Senderowicz","year":"2000","journal-title":"Oncogene"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5130","DOI":"10.1021\/jm300025r","article-title":"Discovery of checkpoint kinase inhibitor (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by structure-based design and optimization of thiophenecarboxamide ureas","volume":"55","author":"Oza","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"35797","DOI":"10.18632\/oncotarget.5929","article-title":"Identification of novel, in vivo active Chk1 inhibitors utilizing structure guided drug design","volume":"6","author":"Massey","year":"2015","journal-title":"Oncotarget"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2394","DOI":"10.1158\/1535-7163.MCT-07-2391","article-title":"Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1","volume":"7","author":"Blasina","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1158\/1535-7163.MCT-10-0928","article-title":"Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening","volume":"10","author":"Guzi","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1517\/17460441.2013.788496","article-title":"Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anticancer therapies","volume":"8","author":"Matthews","year":"2013","journal-title":"Expert Opin. Drug. Discov."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5650","DOI":"10.1158\/1078-0432.CCR-12-1322","article-title":"CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs","volume":"18","author":"Walton","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.18632\/oncotarget.4919","article-title":"The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Emicro-MYC driven B-cell lymphoma","volume":"7","author":"Walton","year":"2016","journal-title":"Oncotarget"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s10637-013-0036-7","article-title":"Characterization and preclinical development of LY2603618: A selective and potent Chk1 inhibitor","volume":"32","author":"King","year":"2014","journal-title":"Investig. New Drugs"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1200\/JCO.2015.64.5788","article-title":"Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer","volume":"34","author":"Hong","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_65","first-page":"4375","article-title":"Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine","volume":"59","author":"Sarkaria","year":"1999","journal-title":"Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"5678","DOI":"10.1093\/nar\/gkp593","article-title":"Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response","volume":"37","author":"Nishida","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/nsmb.2076","article-title":"A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations","volume":"18","author":"Toledo","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1021\/jm101488z","article-title":"Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents","volume":"54","author":"Charrier","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e441","DOI":"10.1038\/cddis.2012.181","article-title":"Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation","volume":"3","author":"Fokas","year":"2012","journal-title":"Cell Death Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"873","DOI":"10.4155\/fmc.15.33","article-title":"Drugging ATR: Progress in the development of specific inhibitors for the treatment of cancer","volume":"7","author":"Foote","year":"2015","journal-title":"Future Med. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1021\/jm301859s","article-title":"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","volume":"56","author":"Foote","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.drudis.2011.12.009","article-title":"Targeting the S and G2 checkpoint to treat cancer","volume":"17","author":"Chen","year":"2012","journal-title":"Drug Discov. Today"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2955","DOI":"10.1158\/1535-7163.MCT-08-0492","article-title":"AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies","volume":"7","author":"Zabludoff","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1038\/cdd.2011.170","article-title":"Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy","volume":"19","author":"Bartucci","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1002\/ijc.25842","article-title":"Checkpoint kinase inhibitor synergizes with DNA-damaging agents in G1 checkpoint-defective neuroblastoma","volume":"129","author":"Xu","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1158\/1535-7163.MCT-11-0406","article-title":"Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites","volume":"11","author":"Montano","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4412","DOI":"10.1158\/1078-0432.CCR-12-3748","article-title":"Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor MK8776","volume":"19","author":"Engelke","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Bryant, C., Rawlinson, R., and Massey, A.J. (2014). Chk1 inhibition as a novel therapeutic strategy for treating triple-negative breast and ovarian cancers. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-570"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5364","DOI":"10.1158\/1078-0432.CCR-12-0961","article-title":"Effects of selective checkpoint kinase 1 inhibition on cytarabine cytotoxicity in acute myelogenous leukemia cells in vitro","volume":"18","author":"Schenk","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"307","DOI":"10.4161\/cbt.19074","article-title":"Evaluation of checkpoint kinase targeting therapy in acute myeloid leukemia with complex karyotype","volume":"13","author":"Didier","year":"2012","journal-title":"Cancer Biol. Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nchembio.573","article-title":"Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR","volume":"7","author":"Reaper","year":"2011","journal-title":"Nat Chem. Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5674","DOI":"10.18632\/oncotarget.2158","article-title":"Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970","volume":"5","author":"Hall","year":"2014","journal-title":"Oncotarget"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Kim, M.K., James, J., and Annunziata, C.M. (2015). Topotecan synergizes with CHEK1 (CHK1) inhibitor to induce apoptosis in ovarian cancer cells. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1231-z"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"6968","DOI":"10.1158\/0008-5472.CAN-13-3369","article-title":"ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses","volume":"74","author":"Josse","year":"2014","journal-title":"Cancer Res."},{"key":"ref_85","first-page":"275","article-title":"Activation of programmed cell death by anticancer agents: Cisplatin as a model system","volume":"2","author":"Eastman","year":"1990","journal-title":"Cancer Cells"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"7265","DOI":"10.1038\/sj.onc.1206933","article-title":"Cisplatin: Mode of cytotoxic action and molecular basis of resistance","volume":"22","author":"Siddik","year":"2003","journal-title":"Oncogene"},{"key":"ref_87","first-page":"983","article-title":"The role of cell cycle progression in cisplatin-induced apoptosis in Chinese hamster ovary cells","volume":"5","author":"Demarcq","year":"1994","journal-title":"Cell Growth Differ."},{"key":"ref_88","first-page":"53","article-title":"A comparison of response to cisplatin, radiation and combined treatment for cells deficient in recombination repair pathways","volume":"25","author":"Raaphorst","year":"2005","journal-title":"Anticancer Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/sj.neo.7900122","article-title":"Cisplatinum and taxol induce different patterns of p53 phosphorylation","volume":"3","author":"Damia","year":"2001","journal-title":"Neoplasia"},{"key":"ref_90","first-page":"207","article-title":"Potentiation of sulphur mustard or cisplatin-induced toxicity by caffeine in Chinese hamster cells correlates with formation of DNA double-strand breaks during replication on a damaged template","volume":"165","author":"Roberts","year":"1986","journal-title":"Mutat. Res."},{"key":"ref_91","first-page":"2275","article-title":"Inhibition of cisplatin-induced ATR activity and enhanced sensitivity to cisplatin","volume":"23","author":"Yazlovitskaya","year":"2003","journal-title":"Anticancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"44289","DOI":"10.18632\/oncotarget.6247","article-title":"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","volume":"6","author":"Vendetti","year":"2015","journal-title":"Oncotarget"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.ygyno.2014.12.035","article-title":"Pharmacologic inhibition of ATR and ATM offers clinically important distinctions to enhancing platinum or radiation response in ovarian, endometrial, and cervical cancer cells","volume":"136","author":"Teng","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1124\/mol.109.055178","article-title":"Cisplatin-induced DNA damage activates replication checkpoint signaling components that differentially affect tumor cell survival","volume":"76","author":"Wagner","year":"2009","journal-title":"Mol. Pharmacol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1097\/IGC.0000000000000014","article-title":"Checkpoint kinase inhibitor AZD7762 overcomes cisplatin resistance in clear cell carcinoma of the ovary","volume":"24","author":"Itamochi","year":"2014","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1158\/1535-7163.MCT-13-0157","article-title":"CHK1\/2 inhibition overcomes the cisplatin resistance of head and neck cancer cells secondary to the loss of functional p53","volume":"12","author":"Gadhikar","year":"2013","journal-title":"Mol. Cancer Ther."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"4630","DOI":"10.1158\/1078-0432.CCR-08-3272","article-title":"PF-00477736 mediates checkpoint kinase 1 signaling pathway and potentiates docetaxel-induced efficacy in xenografts","volume":"15","author":"Zhang","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1158\/1535-7163.MCT-15-0998","article-title":"CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy","volume":"15","author":"Barker","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.bbrc.2011.01.106","article-title":"Inhibition of checkpoint kinase 1 sensitizes lung cancer brain metastases to radiotherapy","volume":"406","author":"Yang","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1158\/1078-0432.CCR-09-3277","article-title":"In vitro and in vivo radiation sensitization of human tumor cells by a novel checkpoint kinase inhibitor, AZD7762","volume":"16","author":"Mitchell","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1158\/1535-7163.MCT-16-0239","article-title":"Radiosensitization by the ATR Inhibitor AZD6738 through Generation of Acentric Micronuclei","volume":"16","author":"Dillon","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"34688","DOI":"10.18632\/oncotarget.9156","article-title":"Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress","volume":"7","author":"Zhang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Kleiman, L.B., Krebs, A.M., Kim, S.Y., Hong, T.S., and Haigis, K.M. (2013). Comparative analysis of radiosensitizers for K-RAS mutant rectal cancers. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082982"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/bjc.2012.265","article-title":"Targeting radiation-resistant hypoxic tumour cells through ATR inhibition","volume":"107","author":"Pires","year":"2012","journal-title":"Br. J. Cancer"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/nrc2344","article-title":"Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability","volume":"8","author":"Bristow","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/379088a0","article-title":"Koch Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours","volume":"379","author":"Graeber","year":"1996","journal-title":"Nature"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3683","DOI":"10.1158\/0008-5472.CAN-13-0110","article-title":"ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status","volume":"73","author":"Huntoon","year":"2013","journal-title":"Cancer Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1124\/mol.110.067199","article-title":"Poly(ADP-Ribose) Polymerase 1 Modulates the Lethality of CHK1 Inhibitors in Carcinoma Cells","volume":"78","author":"Mitchell","year":"2010","journal-title":"Mol. Pharmacol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1124\/mol.112.078907","article-title":"Poly(ADP-ribose) Polymerase 1 Modulates the Lethality of CHK1 Inhibitors in Mammary Tumors","volume":"82","author":"Tang","year":"2012","journal-title":"Mol. Pharmacol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"458","DOI":"10.4161\/cbt.24424","article-title":"PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells","volume":"14","author":"Booth","year":"2013","journal-title":"Cancer Biol. Ther."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"4321","DOI":"10.4161\/cc.10.24.18661","article-title":"Selective radiosensitization of p53 mutant pancreatic cancer cells by combined inhibition of Chk1 and PARP1","volume":"10","author":"Vance","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"C60","DOI":"10.1158\/1535-7163.TARG-15-C60","article-title":"Abstract C60: Pre-clinical efficacy of the ATR inhibitor AZD6738 in combination with the PARP inhibitor olaparib","volume":"14","author":"Lau","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.celrep.2015.12.032","article-title":"Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities","volume":"14","author":"Sanjiv","year":"2016","journal-title":"Cell Rep."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"788","DOI":"10.4161\/cbt.12.9.17673","article-title":"Chk1 inhibition and Wee1 inhibition combine synergistically to impede cellular proliferation","volume":"12","author":"Davies","year":"2011","journal-title":"Cancer Biol. Ther."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.4161\/cc.20899","article-title":"Combined inhibition of Chk1 and Wee1: In vitro synergistic effect translates to tumor growth inhibition in vivo","volume":"11","author":"Carrassa","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1038\/nsmb.2189","article-title":"Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors","volume":"18","author":"Murga","year":"2011","journal-title":"Nat. struct. Mol. Biol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"9693","DOI":"10.1158\/0008-5472.CAN-10-2286","article-title":"Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner","volume":"70","author":"Gilad","year":"2010","journal-title":"Cancer Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.molonc.2011.07.002","article-title":"Targeting ATR and Chk1 kinases for cancer treatment: A new model for new (and old) drugs","volume":"5","author":"Toledo","year":"2011","journal-title":"Mol. Oncol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1172\/JCI58928","article-title":"Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR","volume":"122","author":"Schoppy","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Morgado-Palacin, I., Day, A., Murga, M., Lafarga, V., Anton, M.E., Tubbs, A., Chen, H.-T., Ergen, A.V., Anderson, R., and Bhandoola, A. (2016). Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML. Sci. Signal., 9.","DOI":"10.1126\/scisignal.aad8243"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"13837","DOI":"10.1038\/ncomms13837","article-title":"ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A","volume":"7","author":"Williamson","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"7080","DOI":"10.18632\/oncotarget.6857","article-title":"A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers","volume":"7","author":"Hocke","year":"2016","journal-title":"Oncotarget"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"482","DOI":"10.4161\/cc.8.3.7661","article-title":"Replication stress activates DNA polymerase alpha-associated Chk1","volume":"8","author":"Taricani","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Sultana, R., Abdel-Fatah, T., Perry, C., Moseley, P., Albarakti, N., Mohan, V., Seedhouse, C., Chan, S., and 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.","DOI":"10.1371\/journal.pone.0057098"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"32396","DOI":"10.18632\/oncotarget.6136","article-title":"Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition","volume":"6","author":"Middleton","year":"2015","journal-title":"Oncotarget"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"2835","DOI":"10.1158\/0008-5472.CAN-13-3229","article-title":"ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency","volume":"74","author":"Mohni","year":"2014","journal-title":"Cancer Res."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.canlet.2011.12.038","article-title":"Base Excision Repair and Cancer","volume":"327","author":"Wallace","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/nrm3822","article-title":"Understanding nucleotide excision repair and its roles in cancer and ageing","volume":"15","author":"Marteijn","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.molonc.2015.08.004","article-title":"mTORC1 and DNA-PKcs as novel molecular determinants of sensitivity to Chk1 inhibition","volume":"10","author":"Massey","year":"2016","journal-title":"Mol. Oncol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1476-4598-8-24","article-title":"CHK1 inhibition as a strategy for targeting fanconi anemia (FA) DNA repair pathway deficient tumors","volume":"8","author":"Chen","year":"2009","journal-title":"Mol. Cancer"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"4223","DOI":"10.1182\/blood-2005-10-4240","article-title":"Molecular pathogenesis of Fanconi anemia: Recent progress","volume":"107","author":"Taniguchi","year":"2006","journal-title":"Blood"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1182\/blood-2015-05-644872","article-title":"ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM- defective chronic lymphocytic leukemia cells","volume":"127","author":"Kwok","year":"2016","journal-title":"Blood"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"3474","DOI":"10.1038\/onc.2014.276","article-title":"ATR inhibition preferentially targets homologous recombination-deficient tumor cells","volume":"34","author":"Krajewska","year":"2015","journal-title":"Oncogene"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Mohni, K.N., Thompson, P.S., Luzwick, J.W., Glick, G.G., Pendleton, C.S., Lehmann, B.D., Pietenpol, J.A., and 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.","DOI":"10.1371\/journal.pone.0125482"},{"key":"ref_135","unstructured":"US Food and Drug Administration (2017, April 20). Resources for Information on Approved Drugs, Available online: http:\/\/www.fda.gov\/Drugs\/InformationOnDrugs\/ApprovedDrugs."},{"key":"ref_136","unstructured":"(2017, April 20). European Medicines Agency. Available online: http:\/\/www.ema.europa.eu."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.1200\/JCO.2016.34.15_suppl.2504","article-title":"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","volume":"34","author":"Brown","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1200\/JCO.2016.34.15_suppl.2513","article-title":"Phase I trial of first-in-class ATR inhibitor VX-970 in combination with gemcitabine (Gem) in advanced solid tumors (NCT02157792)","volume":"34","author":"Plummer","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Shapiro, G., Wesolowski, R., Middleton, M., Devoe, C., Constantinidou, A., Papadatos-Pastos, D., Fricano, M., Zhang, Y., Karan, S., and Pollard, J. (2016). Phase 1 trial of first-in-class ATR inhibitor VX-970 in combination with cisplatin (Cis) in patients (pts) with advanced solid tumors (NCT02157792). Cancer Res.","DOI":"10.1158\/1538-7445.AM2016-CT012"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"TPS2603","DOI":"10.1200\/JCO.2016.34.15_suppl.TPS2603","article-title":"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","volume":"34","author":"Dillon","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s00280-014-2380-5","article-title":"Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors","volume":"73","author":"Sausville","year":"2014","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"e1012976","DOI":"10.1080\/23723556.2015.1012976","article-title":"Trial Watch: Targeting ATM-CHK2 and ATR-CHK1 pathways for anticancer therapy","volume":"2","author":"Manic","year":"2015","journal-title":"Mol. Cell. Oncol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1200\/JCO.2014.57.5027","article-title":"Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors","volume":"33","author":"Daud","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"6723","DOI":"10.1158\/1078-0432.CCR-12-2442","article-title":"Phase I and pharmacologic trial of cytosine arabinoside with the selective checkpoint 1 inhibitor Sch 900776 in refractory acute leukemias","volume":"18","author":"Karp","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1097\/CAD.0000000000000278","article-title":"Phase I study of LY2603618, a CHK1 inhibitor, in combination with gemcitabine in Japanese patients with solid tumors","volume":"26","author":"Doi","year":"2015","journal-title":"Anticancer Drugs"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1159\/000448621","article-title":"Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors","volume":"91","author":"Calvo","year":"2016","journal-title":"Oncology"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s10637-016-0368-1","article-title":"Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer","volume":"34","author":"Scagliotti","year":"2016","journal-title":"Investig. New Drugs"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/9\/5\/41\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:33:59Z","timestamp":1760207639000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/9\/5\/41"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,27]]},"references-count":147,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2017,5]]}},"alternative-id":["cancers9050041"],"URL":"https:\/\/doi.org\/10.3390\/cancers9050041","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,27]]}}}