{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T07:51:36Z","timestamp":1776844296812,"version":"3.51.2"},"reference-count":48,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2021,7,31]],"date-time":"2021-07-31T00:00:00Z","timestamp":1627689600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,31]],"date-time":"2021-07-31T00:00:00Z","timestamp":1627689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["FWF SFB F4702, P29018-B30"],"award-info":[{"award-number":["FWF SFB F4702, P29018-B30"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Blood Cancer J."],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mutations of calreticulin (CALR) are the second most prevalent driver mutations in essential thrombocythemia and primary myelofibrosis. To identify potential targeted therapies for <jats:italic>CALR<\/jats:italic> mutated myeloproliferative neoplasms, we searched for small molecules that selectively inhibit the growth of <jats:italic>CALR<\/jats:italic> mutated cells using high-throughput drug screening. We investigated 89 172 compounds using isogenic cell lines carrying <jats:italic>CALR<\/jats:italic> mutations and identified synthetic lethality with compounds targeting the ATR-CHK1 pathway. The selective inhibitory effect of these compounds was validated in a co-culture assay of <jats:italic>CALR<\/jats:italic> mutated and wild-type cells. Of the tested compounds, CHK1 inhibitors potently depleted <jats:italic>CALR<\/jats:italic> mutated cells, allowing wild-type cell dominance in the co-culture over time. Neither <jats:italic>CALR<\/jats:italic> deficient cells nor <jats:italic>JAK2V617F<\/jats:italic> mutated cells showed hypersensitivity to ATR-CHK1 inhibition, thus suggesting specificity for the oncogenic activation by the mutant CALR. CHK1 inhibitors induced replication stress in <jats:italic>CALR<\/jats:italic> mutated cells revealed by elevated pan-nuclear staining for \u03b3H2AX and hyperphosphorylation of RPA2. This was accompanied by S-phase cell cycle arrest due to incomplete DNA replication. Transcriptomic and phosphoproteomic analyses revealed a replication stress signature caused by oncogenic CALR, suggesting an intrinsic vulnerability to CHK1 perturbation. This study reveals the ATR-CHK1 pathway as a potential therapeutic target in <jats:italic>CALR<\/jats:italic> mutated hematopoietic cells.<\/jats:p>","DOI":"10.1038\/s41408-021-00531-2","type":"journal-article","created":{"date-parts":[[2021,7,31]],"date-time":"2021-07-31T14:02:54Z","timestamp":1627740174000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["High-throughput drug screening identifies the ATR-CHK1 pathway as a therapeutic vulnerability of CALR mutated hematopoietic cells"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3500-0516","authenticated-orcid":false,"given":"Ruochen","family":"Jia","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3303-8059","authenticated-orcid":false,"given":"Leon","family":"Kutzner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Koren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathrin","family":"Runggatscher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"M\u00e1jek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9 C.","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2975-8969","authenticated-orcid":false,"given":"Michael","family":"Schuster","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6091-3088","authenticated-orcid":false,"given":"Christoph","family":"Bock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1853-0424","authenticated-orcid":false,"given":"Joanna I.","family":"Loizou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0855-8343","authenticated-orcid":false,"given":"Stefan","family":"Kubicek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6997-8539","authenticated-orcid":false,"given":"Robert","family":"Kralovics","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,7,31]]},"reference":[{"key":"531_CR1","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1056\/NEJMoa065202","volume":"356","author":"LM Scott","year":"2007","unstructured":"Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356:459\u201368.","journal-title":"N Engl J Med"},{"key":"531_CR2","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1038\/nature03546","volume":"434","author":"C James","year":"2005","unstructured":"James C, Ugo V, Le Cou\u00e9dic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144\u20138.","journal-title":"Nature."},{"key":"531_CR3","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1016\/S0140-6736(05)71142-9","volume":"365","author":"EJ Baxter","year":"2005","unstructured":"Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054\u201361.","journal-title":"Lancet."},{"key":"531_CR4","doi-asserted-by":"publisher","first-page":"e270","DOI":"10.1371\/journal.pmed.0030270","volume":"3","author":"Y Pikman","year":"2006","unstructured":"Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3:e270.","journal-title":"PLoS Med"},{"key":"531_CR5","doi-asserted-by":"publisher","first-page":"1779","DOI":"10.1056\/NEJMoa051113","volume":"352","author":"R Kralovics","year":"2005","unstructured":"Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779\u201390.","journal-title":"N Engl J Med"},{"key":"531_CR6","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.ccr.2005.03.023","volume":"7","author":"RL Levine","year":"2005","unstructured":"Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387\u201397.","journal-title":"Cancer Cell"},{"key":"531_CR7","doi-asserted-by":"publisher","first-page":"2391","DOI":"10.1056\/NEJMoa1312542","volume":"369","author":"J Nangalia","year":"2013","unstructured":"Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391\u2013405.","journal-title":"N Engl J Med"},{"key":"531_CR8","doi-asserted-by":"publisher","first-page":"2379","DOI":"10.1056\/NEJMoa1311347","volume":"369","author":"T Klampfl","year":"2013","unstructured":"Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379\u201390.","journal-title":"N Engl J Med"},{"key":"531_CR9","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1056\/NEJMoa1409002","volume":"372","author":"AM Vannucchi","year":"2015","unstructured":"Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372:426\u201335.","journal-title":"N Engl J Med"},{"key":"531_CR10","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1056\/NEJMoa1110557","volume":"366","author":"S Verstovsek","year":"2012","unstructured":"Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799\u2013807.","journal-title":"N Engl J Med"},{"key":"531_CR11","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1056\/NEJMoa1110556","volume":"366","author":"C Harrison","year":"2012","unstructured":"Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787\u201398.","journal-title":"N Engl J Med"},{"key":"531_CR12","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1182\/blood-2015-11-681932","volume":"127","author":"I Chachoua","year":"2016","unstructured":"Chachoua I, Pecquet C, El-Khoury M, Nivarthi H, Albu RI, Marty C, et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood. 2016;127:1325\u201335.","journal-title":"Blood."},{"key":"531_CR13","doi-asserted-by":"publisher","first-page":"2669","DOI":"10.1182\/blood-2018-09-874578","volume":"133","author":"C Pecquet","year":"2019","unstructured":"Pecquet C, Chachoua I, Roy A, Balligand T, Vertenoeil G, Leroy E, et al. Calreticulin mutants as oncogenic rogue chaperones for TpoR and traffic-defective pathogenic TpoR mutants. Blood. 2019;133:2669\u201381.","journal-title":"Blood."},{"key":"531_CR14","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1182\/blood-2015-11-679571","volume":"127","author":"C Marty","year":"2016","unstructured":"Marty C, Pecquet C, Nivarthi H, El-Khoury M, Chachoua I, Tulliez M, et al. Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis. Blood. 2016;127:1317\u201324.","journal-title":"Blood."},{"key":"531_CR15","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1158\/2159-8290.CD-15-1434","volume":"6","author":"S Elf","year":"2016","unstructured":"Elf S, Abdelfattah NS, Chen E, Perales-Pat\u00f3n J, Rosen EA, Ko A, et al. Mutant calreticulin requires both its mutant C-terminus and the thrombopoietin receptor for oncogenic transformation. Cancer Discov. 2016;6:368\u201381.","journal-title":"Cancer Discov"},{"key":"531_CR16","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.1038\/leu.2016.32","volume":"30","author":"H Nivarthi","year":"2016","unstructured":"Nivarthi H, Chen D, Cleary C, Kubesova B, J\u00e4ger R, Bogner E, et al. Thrombopoietin receptor is required for the oncogenic function of CALR mutants. Leukemia. 2016;30:1759\u201363.","journal-title":"Leukemia."},{"key":"531_CR17","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1182\/blood-2015-09-671172","volume":"127","author":"M Araki","year":"2016","unstructured":"Araki M, Yang Y, Masubuchi N, Hironaka Y, Takei H, Morishita S, et al. Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms. Blood. 2016;127:1307\u201316.","journal-title":"Blood."},{"key":"531_CR18","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.1182\/blood-2013-11-539098","volume":"123","author":"E Rumi","year":"2014","unstructured":"Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, Milosevic JD, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2014;123:1544\u201351.","journal-title":"Blood"},{"key":"531_CR19","doi-asserted-by":"publisher","first-page":"2848","DOI":"10.1182\/blood-2017-05-784942","volume":"130","author":"M Nieborowska-Skorska","year":"2017","unstructured":"Nieborowska-Skorska M, Maifrede S, Dasgupta Y, Sullivan K, Flis S, Le BV, et al. Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms. Blood. 2017;130:2848\u201359.","journal-title":"Blood."},{"key":"531_CR20","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1038\/leu.2015.277","volume":"30","author":"D Pietra","year":"2016","unstructured":"Pietra D, Rumi E, Ferretti VV, Di Buduo CA, Milanesi C, Cavalloni C, et al. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia. 2016;30:431\u20138.","journal-title":"Leukemia."},{"key":"531_CR21","doi-asserted-by":"publisher","first-page":"1920","DOI":"10.1182\/blood.2020006264","volume":"137","author":"R Jia","year":"2021","unstructured":"Jia R, Balligand T, Atamanyuk V, Nivarthi H, Xu E, Kutzner L, et al. Hematoxylin binds to mutant calreticulin and disrupts its abnormal interaction with thrombopoietin receptor. Blood. 2021;137:1920\u201331.","journal-title":"Blood."},{"key":"531_CR22","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1172\/JCI58928","volume":"122","author":"DW Schoppy","year":"2012","unstructured":"Schoppy DW, Ragland RL, Gilad O, Shastri N, Peters AA, Murga M, et al. Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR. J Clin Invest. 2012;122:241\u201352.","journal-title":"J Clin Invest"},{"key":"531_CR23","doi-asserted-by":"publisher","first-page":"9693","DOI":"10.1158\/0008-5472.CAN-10-2286","volume":"70","author":"O Gilad","year":"2010","unstructured":"Gilad O, Nabet BY, Ragland RL, Schoppy DW, Smith KD, Durham AC, et al. Combining ATR suppression with oncogenic ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Res. 2010;70:9693\u2013702.","journal-title":"Cancer Res"},{"key":"531_CR24","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1016\/j.ccr.2008.11.003","volume":"14","author":"V Nogueira","year":"2008","unstructured":"Nogueira V, Park Y, Chen CC, Xu PZ, Chen ML, Tonic I, et al. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell. 2008;14:458\u201370.","journal-title":"Cancer Cell"},{"key":"531_CR25","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1158\/2159-8290.CD-17-1461","volume":"8","author":"P Kotsantis","year":"2018","unstructured":"Kotsantis P, Petermann E, Boulton SJ. Mechanisms of oncogene-induced replication stress: jigsaw falling into place. Cancer Discov. 2018;8:537\u201355.","journal-title":"Cancer Discov"},{"key":"531_CR26","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1177\/108705719900400206","volume":"4","author":"J-H Zhang","year":"1999","unstructured":"Zhang J-H, Chung TDY, Oldenburg KR. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen. 1999;4:67\u201373.","journal-title":"J Biomol Screen"},{"key":"531_CR27","doi-asserted-by":"publisher","first-page":"688","DOI":"10.3324\/haematol.2013.093187","volume":"99","author":"L Chaudhuri","year":"2014","unstructured":"Chaudhuri L, Vincelette ND, Koh BD, Naylor RM, Flatten KS, Peterson KL, et al. CHK1 and WEE1 inhibition combine synergistically to enhance therapeutic efficacy in acute myeloid leukemia ex vivo. Haematologica. 2014;99:688\u201396.","journal-title":"Haematologica."},{"key":"531_CR28","doi-asserted-by":"publisher","first-page":"10966","DOI":"10.18632\/oncotarget.14089","volume":"8","author":"S Hauge","year":"2017","unstructured":"Hauge S, Naucke C, Hasvold G, Joel M, R\u00f8dland GE, Juzenas P, et al. Combined inhibition of Wee1 and Chk1 gives synergistic DNA damage in S-phase due to distinct regulation of CDK activity and CDC45 loading. Oncotarget. 2017;8:10966\u201379.","journal-title":"Oncotarget."},{"key":"531_CR29","first-page":"9776","volume":"43","author":"P Zuazua-Villar","year":"2015","unstructured":"Zuazua-Villar P, Ganesh A, Phear G, Gagou ME, Meuth M. Extensive RPA2 hyperphosphorylation promotes apoptosis in response to DNA replication stress in CHK1 inhibited cells. Nucleic Acids Res. 2015;43:9776\u201387.","journal-title":"Nucleic Acids Res"},{"key":"531_CR30","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1158\/1535-7163.MCT-10-0928","volume":"10","author":"TJ Guzi","year":"2011","unstructured":"Guzi TJ, Paruch K, Dwyer MP, Labroli M, Shanahan F, Davis N, et al. Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. Mol Cancer Ther. 2011;10:591\u2013602.","journal-title":"Mol Cancer Ther"},{"key":"531_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/cpz1.90","volume":"1","author":"Z Xie","year":"2021","unstructured":"Xie Z, Bailey A, Kuleshov MV, Clarke D, Evangelista JE, Jenkins SL, et al. Gene set knowledge discovery with enrichr. Curr Protoc. 2021;1:1\u201351.","journal-title":"Curr Protoc"},{"key":"531_CR32","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-128","volume":"14","author":"EY Chen","year":"2013","unstructured":"Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV, et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics. 2013;14:128.","journal-title":"BMC Bioinformatics"},{"key":"531_CR33","doi-asserted-by":"publisher","first-page":"W90","DOI":"10.1093\/nar\/gkw377","volume":"44","author":"MV Kuleshov","year":"2016","unstructured":"Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44:W90\u20137.","journal-title":"Nucleic Acids Res"},{"key":"531_CR34","doi-asserted-by":"publisher","first-page":"31458","DOI":"10.1074\/jbc.M113.511337","volume":"288","author":"BM Sirbu","year":"2013","unstructured":"Sirbu BM, McDonald WH, Dungrawala H, Badu-Nkansah A, Kavanaugh GM, Chen Y, et al. Identification of proteins at active, stalled, and collapsed replication forks using isolation of proteins on nascent DNA (iPOND) coupled with mass spectrometry. J Biol Chem. 2013;288:31458\u201367.","journal-title":"J Biol Chem"},{"key":"531_CR35","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1038\/ncb2918","volume":"16","author":"C Alabert","year":"2014","unstructured":"Alabert C, Bukowski-Wills JC, Lee SB, Kustatscher G, Nakamura K, de Lima Alves F, et al. Nascent chromatin capture proteomics determines chromatin dynamics during DNA replication and identifies unknown fork components. Nat Cell Biol. 2014;16:281\u201391.","journal-title":"Nat Cell Biol"},{"key":"531_CR36","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1038\/leu.2013.102","volume":"27","author":"C Marty","year":"2013","unstructured":"Marty C, Lacout C, Droin N, Le Cou\u00e9dic JP, Ribrag V, Solary E, et al. A role for reactive oxygen species in JAK2V617F myeloproliferative neoplasm progression. Leukemia. 2013;27:2187\u201395.","journal-title":"Leukemia."},{"key":"531_CR37","doi-asserted-by":"publisher","first-page":"15190","DOI":"10.1073\/pnas.1401873111","volume":"111","author":"E Chen","year":"2014","unstructured":"Chen E, Ahn JS, Massie CE, Clynes D, Godfrey AL, Li J, et al. JAK2V617F promotes replication fork stalling with disease-restricted impairment of the intra-S checkpoint response. Proc Natl Acad Sci. 2014;111:15190\u20135.","journal-title":"Proc Natl Acad Sci"},{"key":"531_CR38","doi-asserted-by":"publisher","first-page":"39517","DOI":"10.1074\/jbc.M605121200","volume":"281","author":"E Olson","year":"2006","unstructured":"Olson E, Nievera CJ, Klimovich V, Fanning E, Wu X. RPA2 is a direct downstream target for ATR to regulate the S-phase checkpoint. J Biol Chem. 2006;281:39517\u201333.","journal-title":"J Biol Chem"},{"key":"531_CR39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/cancers11030355","volume":"11","author":"E Moeglin","year":"2019","unstructured":"Moeglin E, et al. Uniform widespread nuclear phosphorylation of histone H2AX is an indicator of lethal DNA replication stress. Cancers. 2019;11:1\u201322.","journal-title":"Cancers"},{"key":"531_CR40","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1038\/nsmb.2076","volume":"18","author":"LI Toledo","year":"2011","unstructured":"Toledo LI, Murga M, Zur R, Soria R, Rodriguez A, Martinez S, et al. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol. 2011;18:721\u20137.","journal-title":"Nat Struct Mol Biol"},{"key":"531_CR41","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1016\/j.cell.2014.01.001","volume":"156","author":"LI Toledo","year":"2014","unstructured":"Toledo LI, Altmeyer M, Rask MB, Lukas C, Larsen DH, Povlsen LK, et al. ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell. 2014;156:374.","journal-title":"Cell."},{"key":"531_CR42","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/s41586-019-1367-0","volume":"571","author":"AS Nam","year":"2019","unstructured":"Nam AS, Kim KT, Chaligne R, Izzo F, Ang C, Taylor J, et al. Somatic mutations and cell identity linked by genotyping of transcriptomes. Nature. 2019;571:355\u201360.","journal-title":"Nature."},{"key":"531_CR43","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1038\/nature05953","volume":"448","author":"D Dominguez-Sola","year":"2007","unstructured":"Dominguez-Sola D, Ying CY, Grandori C, Ruggiero L, Chen B, Li M, et al. Non-transcriptional control of DNA replication by c-Myc. Nature. 2007;448:445\u201351.","journal-title":"Nature"},{"key":"531_CR44","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1038\/leu.2016.280","volume":"31","author":"K Kollmann","year":"2017","unstructured":"Kollmann K, Warsch W, Gonzalez-Arias C, Nice FL, Avezov E, Milburn J, et al. A novel signalling screen demonstrates that CALR mutations activate essential MAPK signalling and facilitate megakaryocyte differentiation. Leukemia. 2017;31:934\u201344.","journal-title":"Leukemia."},{"key":"531_CR45","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.ccell.2021.02.014","volume":"39","author":"A Thomas","year":"2021","unstructured":"Thomas A, Takahashi N, Rajapakse VN, Zhang X, Sun Y, Ceribelli M, et al. Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress. Cancer Cell. 2021;39:566\u201379.","journal-title":"Cancer Cell"},{"key":"531_CR46","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1080\/13543784.2018.1508448","volume":"27","author":"K Chamoun","year":"2018","unstructured":"Chamoun K, Borthakur G. Investigational CHK1 inhibitors in early stage clinical trials for acute myeloid leukemia. Expert Opin Investig Drugs. 2018;27:661\u20136.","journal-title":"Expert Opin Investig Drugs"},{"key":"531_CR47","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.radonc.2017.09.043","volume":"126","author":"Z Qiu","year":"2018","unstructured":"Qiu Z, Oleinick NL, Zhang J. ATR\/CHK1 inhibitors and cancer therapy. Radiother Oncol. 2018;126:450\u201364.","journal-title":"Radiother Oncol"},{"key":"531_CR48","doi-asserted-by":"publisher","first-page":"D442","DOI":"10.1093\/nar\/gky1106","volume":"47","author":"Y Perez-Riverol","year":"2019","unstructured":"Perez-Riverol Y, Csordas A, Bai J, Bernal-Llinares M, Hewapathirana S, Kundu DJ, et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res. 2019;47:D442\u201350.","journal-title":"Nucleic Acids Res"}],"container-title":["Blood Cancer Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41408-021-00531-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41408-021-00531-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41408-021-00531-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T18:21:58Z","timestamp":1669918918000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41408-021-00531-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,31]]},"references-count":48,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["531"],"URL":"https:\/\/doi.org\/10.1038\/s41408-021-00531-2","relation":{},"ISSN":["2044-5385"],"issn-type":[{"value":"2044-5385","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,31]]},"assertion":[{"value":"3 May 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 July 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 July 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 July 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"137"}}