{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T21:52:38Z","timestamp":1781646758530,"version":"3.54.5"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":4,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100017590","name":"Universit\u00e4tsklinikum Essen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017590","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Ewing Sarcoma (EwS) is a highly aggressive malignancy predominantly affecting young individuals, with poor prognosis in metastatic or relapsed cases. This study investigates the therapeutic potential of ataxia telangiectasia and Rad3-related protein (ATR) inhibition using the selective small-molecule inhibitor elimusertib, both as a monotherapy and in combination with cytotoxic drugs or radiotherapy. Elimusertib significantly inhibited cell proliferation and induced apoptosis in EwS cell lines. In a chorioallantoic membrane (CAM) model, elimusertib suppressed tumor initiation and reduced tumor volume. Notably, elimusertib exhibited synergistic effects with standard chemotherapeutics and radiation, enhancing antitumor efficacy. These preclinical findings suggest that ATR inhibition by elimusertib may enhance current EwS therapies and enable dose reduction of cytotoxic drugs. Further clinical evaluation is warranted to validate these findings and explore elimusertib\u2019s translational potential in EwS treatment.<\/jats:p>","DOI":"10.1038\/s41598-026-41751-5","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:36:44Z","timestamp":1774611404000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Elimusertib enhances cytotoxic effects of conventional chemotherapy and sensitizes to radiation in preclinical Ewing sarcoma models"],"prefix":"10.1038","volume":"16","author":[{"given":"Leonhard","family":"Koch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Kerkhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Bretschneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samet","family":"Dayi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Plaumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahareh","family":"Sadeghi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Maa\u00dfen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Hillesheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Kuballa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Schaefer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Rauh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Grunewald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e4re","family":"von Neubeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uta","family":"Dirksen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"issue":"1","key":"41751_CR1","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41572-018-0003-x","volume":"4","author":"TP Gr\u00fcnewald","year":"2018","unstructured":"Gr\u00fcnewald, T. P. et al. Ewing sarcoma. Nat. Rev. Dis. Prim. 4(1), 5 (2018).","journal-title":"Nat. Rev. Dis. Prim."},{"key":"41751_CR2","doi-asserted-by":"crossref","unstructured":"Z\u00f6llner, S. K. et al. Ewing sarcoma-diagnosis, treatment, clinical challenges and future perspectives. J. Clin. Med. 10(8), 1685 (2021).","DOI":"10.3390\/jcm10081685"},{"key":"41751_CR3","doi-asserted-by":"crossref","unstructured":"Herrad\u00f3n, E. et al. Cardiovascular toxicity induced by chronic vincristine treatment. Front. Pharmacol. 12, 692970 (2021).","DOI":"10.3389\/fphar.2021.692970"},{"key":"41751_CR4","doi-asserted-by":"crossref","unstructured":"Yang, Q. Y. et al. Vincristine-induced peripheral neuropathy in childhood acute lymphoblastic leukemia: genetic variation as a potential risk factor. Front. Pharmacol. 12, 771487 (2021).","DOI":"10.3389\/fphar.2021.771487"},{"issue":"6","key":"41751_CR5","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1007\/s00210-023-02382-z","volume":"396","author":"P Dulf","year":"2023","unstructured":"Dulf, P. et al. Doxorubicin-induced acute cardiotoxicity is associated with increased oxidative stress, autophagy, and inflammation in a murine model. Naunyn. Schmiedebergs Arch. Pharmacol. 396 (6), 1105\u20131115 (2023).","journal-title":"Naunyn. Schmiedebergs Arch. Pharmacol."},{"issue":"2","key":"41751_CR6","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1002\/j.1875-9114.1984.tb03318.x","volume":"4","author":"JA Sinkule","year":"1984","unstructured":"Sinkule, J. A. Etoposide: a semisynthetic epipodophyllotoxin. Chemistry, pharmacology, pharmacokinetics, adverse effects and use as an antineoplastic agent. Pharmacotherapy 4 (2), 61\u201373 (1984).","journal-title":"Pharmacotherapy"},{"issue":"Suppl 2","key":"41751_CR7","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1159\/000073351","volume":"65","author":"J Klastersky","year":"2003","unstructured":"Klastersky, J. Side effects of ifosfamide. Oncology 65 (Suppl 2), 7\u201310 (2003).","journal-title":"Oncology"},{"issue":"7","key":"41751_CR8","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1097\/FPC.0b013e32833ffb56","volume":"21","author":"CF Thorn","year":"2011","unstructured":"Thorn, C. F. et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genom. 21(7), 440\u2013446 (2011).","journal-title":"Pharmacogenet Genom."},{"issue":"11","key":"41751_CR9","doi-asserted-by":"publisher","first-page":"2607","DOI":"10.3390\/cancers13112607","volume":"13","author":"S Zahnreich","year":"2021","unstructured":"Zahnreich, S. & Schmidberger, H. Childhood cancer: Occurrence, treatment and risk of second primary malignancies. Cancers 13(11), 2607 (2021).","journal-title":"Cancers"},{"issue":"2","key":"41751_CR10","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.ijrobp.2022.07.1840","volume":"115","author":"SK Ahmed","year":"2023","unstructured":"Ahmed, S. K. et al. Analysis of local control outcomes and clinical prognostic factors in localized pelvic ewing sarcoma patients treated with radiation therapy: A report from the children\u2019s oncology group. Int. J. Radiat. Oncol. Biol. Phys. 115(2), 337\u2013346 (2023).","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"issue":"3","key":"41751_CR11","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1002\/cncr.29065","volume":"121","author":"SG DuBois","year":"2015","unstructured":"DuBois, S. G. et al. Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children\u2019s Oncology Group. Cancer 121 (3), 467\u2013475 (2015).","journal-title":"Cancer"},{"issue":"4","key":"41751_CR12","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1002\/pbc.23040","volume":"57","author":"M Stahl","year":"2011","unstructured":"Stahl, M. et al. Risk of recurrence and survival after relapse in patients with Ewing sarcoma. Pediatr. Blood Cancer. 57 (4), 549\u2013553 (2011).","journal-title":"Pediatr. Blood Cancer"},{"issue":"3","key":"41751_CR13","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1023\/A:1008208511815","volume":"9","author":"M Paulussen","year":"1998","unstructured":"Paulussen, M. et al. Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies: European Intergroup Cooperative Ewing Sarcoma Studies. Ann. Oncol. 9(3), 275\u2013281 (1998).","journal-title":"Ann. Oncol."},{"key":"41751_CR14","unstructured":"Yustein, J. T. & Ewing, F. D. V. EWS-FLI1 Regulates Genotoxic Stress Response in Ewing\u00a0(2015)."},{"issue":"20","key":"41751_CR15","doi-asserted-by":"publisher","first-page":"15173","DOI":"10.3390\/ijms242015173","volume":"24","author":"M Yasir","year":"2023","unstructured":"Yasir, M., Park, J. & Chun, W. EWS\/FLI1 characterization, activation, repression, target genes and therapeutic opportunities in Ewing Sarcoma. Int. J. Mol. Sci. 24(20), 15173 (2023).","journal-title":"Int. J. Mol. Sci."},{"issue":"5868","key":"41751_CR16","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.1126\/science.1140735","volume":"319","author":"TD Halazonetis","year":"2008","unstructured":"Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319 (5868), 1352\u20131355 (2008).","journal-title":"Science"},{"issue":"8","key":"41751_CR17","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/nrm2450","volume":"9","author":"KA Cimprich","year":"2008","unstructured":"Cimprich, K. A. & Cortez, D. ATR: an essential regulator of genome integrity. Nat. Rev. Mol. Cell. Biol. 9 (8), 616\u2013627 (2008).","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"issue":"1","key":"41751_CR18","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1038\/ncb2897","volume":"16","author":"MK Zeman","year":"2014","unstructured":"Zeman, M. K. & Cimprich, K. A. Causes and consequences of replication stress. Nat. Cell. Biol. 16 (1), 2\u20139 (2014).","journal-title":"Nat. Cell. Biol."},{"key":"41751_CR19","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.pharmthera.2014.12.001","volume":"149","author":"AM Weber","year":"2015","unstructured":"Weber, A. M. & Ryan, A. J. ATM and ATR as therapeutic targets in cancer. Pharmacol. Ther. 149, 124\u2013138 (2015).","journal-title":"Pharmacol. Ther."},{"issue":"1","key":"41751_CR20","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/s41573-022-00558-5","volume":"22","author":"A da Costa","year":"2023","unstructured":"da Costa, A. et al. Targeting replication stress in cancer therapy. Nat. Rev. Drug Discov. 22(1), 38\u201358 (2023).","journal-title":"Nat. Rev. Drug Discov."},{"issue":"37","key":"41751_CR21","doi-asserted-by":"publisher","first-page":"58759","DOI":"10.18632\/oncotarget.11643","volume":"7","author":"M Nieto-Soler","year":"2016","unstructured":"Nieto-Soler, M. et al. Efficacy of ATR inhibitors as single agents in Ewing sarcoma. Oncotarget 7 (37), 58759\u201358767 (2016).","journal-title":"Oncotarget"},{"issue":"10","key":"41751_CR22","doi-asserted-by":"publisher","first-page":"1603","DOI":"10.1158\/1541-7786.MCR-20-0091","volume":"18","author":"T Hack","year":"2020","unstructured":"Hack, T. et al. Exposure of patient-derived mesenchymal stromal cells to TGFB1 supports fibrosis induction in a pediatric acute megakaryoblastic leukemia model. Mol. Cancer Res. 18(10), 1603\u20131612 (2020).","journal-title":"Mol. Cancer Res."},{"issue":"21","key":"41751_CR23","doi-asserted-by":"publisher","first-page":"8770","DOI":"10.1158\/0008-5472.CAN-10-1093","volume":"70","author":"J Potratz","year":"2010","unstructured":"Potratz, J. et al. Synthetic lethality screens reveal RPS6 and MST1R as modifiers of insulin-like growth factor-1 receptor inhibitor activity in childhood sarcomas. Cancer Res. 70(21), 8770\u20138781 (2010).","journal-title":"Cancer Res."},{"issue":"5","key":"41751_CR24","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1016\/j.molonc.2015.12.009","volume":"10","author":"J Potratz","year":"2015","unstructured":"Potratz, J. et al. Receptor tyrosine kinase gene expression profiles of Ewing sarcomas reveal ROR1 as a potential therapeutic target in metastatic disease. Mol. Oncol. 10 (5), 677\u2013692 (2015).","journal-title":"Mol. Oncol."},{"issue":"1","key":"41751_CR25","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13018-022-02931-x","volume":"17","author":"W Guder","year":"2022","unstructured":"Guder, W. et al. 5-ALA-mediated fluorescence of musculoskeletal tumors in a chick chorio-allantoic membrane model: preclinical in vivo qualification analysis as a fluorescence-guided surgery agent in orthopedic oncology. J. Orthop. Surg, Res. 17(1), 34 (2022).","journal-title":"J. Orthop. Surg, Res."},{"key":"41751_CR26","doi-asserted-by":"crossref","unstructured":"Kerkhoff, M. et al. Evaluation of the effect of photodynamic therapy on CAM-grown sarcomas. Bioengineering 10(4), 464 (2023).","DOI":"10.3390\/bioengineering10040464"},{"key":"41751_CR27","doi-asserted-by":"publisher","DOI":"10.3390\/bioengineering10040464","author":"M Kerkhoff","year":"2023","unstructured":"Kerkhoff, M. et al. Evaluation of the effect of photodynamic therapy on CAM-grown sarcomas.. Bioengineering https:\/\/doi.org\/10.3390\/bioengineering10040464 (2023).","journal-title":"Bioengineering"},{"key":"41751_CR28","doi-asserted-by":"crossref","unstructured":"Sys, G. M. L. et al. The in ovo CAM-assay as a xenograft model for sarcoma. 77, e50522 (2013).","DOI":"10.3791\/50522-v"},{"issue":"W1","key":"41751_CR29","doi-asserted-by":"publisher","first-page":"W739","DOI":"10.1093\/nar\/gkac382","volume":"50","author":"A Ianevski","year":"2022","unstructured":"Ianevski, A., Giri, A. K. & Aittokallio, T. SynergyFinder 3.0: an interactive analysis and consensus interpretation of multi-drug synergies across multiple samples. Nucleic Acids Res. 50 (W1), W739\u2013W743 (2022).","journal-title":"Nucleic Acids Res."},{"issue":"19","key":"41751_CR30","doi-asserted-by":"publisher","first-page":"5213","DOI":"10.1158\/1078-0432.CCR-21-1032","volume":"27","author":"T Yap","year":"2021","unstructured":"Yap, T. et al. Ceralasertib (AZD6738), an oral ATR kinase inhibitor, in combination with carboplatin in patients with advanced solid tumors: A phase I study. Clin. Cancer Res. 27(19), 5213\u20135224 (2021).","journal-title":"Clin. Cancer Res."},{"issue":"2","key":"41751_CR31","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.annonc.2021.10.009","volume":"33","author":"R Kim","year":"2022","unstructured":"Kim, R. et al. Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced\/metastatic melanoma who have failed prior anti-PD-1 therapy. Ann. Oncol. 33 (2), 193\u2013203 (2022).","journal-title":"Ann. Oncol."},{"issue":"12","key":"41751_CR32","doi-asserted-by":"publisher","first-page":"4972","DOI":"10.1158\/0008-5472.CAN-09-3573","volume":"70","author":"MA Morgan","year":"2010","unstructured":"Morgan, M. A. et al. Mechanism of radiosensitization by the Chk1\/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair. Cancer Res. 70 (12), 4972\u20134981 (2010).","journal-title":"Cancer Res."},{"issue":"7","key":"41751_CR33","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.1158\/0008-5472.CAN-11-3648","volume":"72","author":"JC Brenner","year":"2012","unstructured":"Brenner, J. C. et al. PARP-1 inhibition as a targeted strategy to treat Ewing\u2019s Sarcoma. Cancer Res. 72(7), 1608\u20131613 (2012).","journal-title":"Cancer Res."},{"issue":"7391","key":"41751_CR34","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1038\/nature11005","volume":"483","author":"MJ Garnett","year":"2012","unstructured":"Garnett, M. J. et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483 (7391), 570\u2013575 (2012).","journal-title":"Nature"},{"issue":"1","key":"41751_CR35","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1186\/1471-2407-14-813","volume":"14","author":"E Choy","year":"2014","unstructured":"Choy, E. et al. Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BMC Cancer. 14 (1), 813 (2014).","journal-title":"BMC Cancer"},{"issue":"6","key":"41751_CR36","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/j.molcel.2017.05.015","volume":"66","author":"A Blackford","year":"2017","unstructured":"Blackford, A. & Jackson, S. ATM, ATR, and DNA-PK: The trinity at the heart of the DNA damage response. Mol. Cell 66(6), 801\u2013817 (2017).","journal-title":"Mol. Cell"},{"key":"41751_CR37","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a012716","author":"A Mar\u00e9chal","year":"2013","unstructured":"Mar\u00e9chal, A. & Zou, L. DNA damage sensing by the ATM and ATR kinases.. Cold Spring Harb. Perspect. Biol. https:\/\/doi.org\/10.1101\/cshperspect.a012716 (2013).","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"41751_CR38","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2019.107450","volume":"207","author":"A Bradbury","year":"2020","unstructured":"Bradbury, A. et al. Targeting ATR as cancer therapy: A new era for synthetic lethality and synergistic combinations?. Pharmacol. Ther. 207, 107450 (2020).","journal-title":"Pharmacol. Ther."},{"key":"41751_CR39","doi-asserted-by":"crossref","unstructured":"Pusch, F. et al. Elimusertib outperforms standard of care chemotherapy in preclinical patient-derived pediatric solid tumor models. bioRxiv, p. 2022.11.10.515290 (2022).","DOI":"10.1101\/2022.11.10.515290"},{"issue":"4","key":"41751_CR40","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1158\/1535-7163.MCT-23-0094","volume":"23","author":"F Pusch","year":"2024","unstructured":"Pusch, F. et al. Elimusertib has antitumor activity in preclinical patient-derived pediatric solid tumor models. Mol. Cancer Ther. 23(4), 507\u2013519 (2024).","journal-title":"Mol. Cancer Ther."},{"issue":"7","key":"41751_CR41","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1038\/s41416-019-0565-8","volume":"121","author":"NR Jette","year":"2019","unstructured":"Jette, N. R. et al. Combined poly-ADP ribose polymerase and ataxia-telangiectasia mutated\/Rad3-related inhibition targets ataxia-telangiectasia mutated-deficient lung cancer cells. Br. J. Cancer. 121 (7), 600\u2013610 (2019).","journal-title":"Br. J. Cancer"},{"issue":"25","key":"41751_CR42","doi-asserted-by":"publisher","first-page":"4869","DOI":"10.1038\/s41388-020-1328-y","volume":"39","author":"RL Lloyd","year":"2020","unstructured":"Lloyd, R. L. et al. Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells. Oncogene 39 (25), 4869\u20134883 (2020).","journal-title":"Oncogene"},{"issue":"6","key":"41751_CR43","doi-asserted-by":"publisher","first-page":"3377","DOI":"10.3892\/or.2017.5580","volume":"37","author":"S Liu","year":"2017","unstructured":"Liu, S. et al. Inhibition of ATR potentiates the cytotoxic effect of gemcitabine on pancreatic cancer cells through enhancement of DNA damage and abrogation of ribonucleotide reductase induction by gemcitabine. Oncol. Rep. 37 (6), 3377\u20133386 (2017).","journal-title":"Oncol. Rep."},{"issue":"23","key":"41751_CR44","doi-asserted-by":"publisher","first-page":"6968","DOI":"10.1158\/0008-5472.CAN-13-3369","volume":"74","author":"R Joss\u00e9","year":"2014","unstructured":"Joss\u00e9, R. et al. 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\u20136979 (2014).","journal-title":"Cancer Res."},{"issue":"42","key":"41751_CR45","doi-asserted-by":"publisher","first-page":"44289","DOI":"10.18632\/oncotarget.6247","volume":"6","author":"FP Vendetti","year":"2015","unstructured":"Vendetti, F. P. et al. 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\u201344305 (2015).","journal-title":"Oncotarget"},{"issue":"1","key":"41751_CR46","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1002\/ijc.30373","volume":"140","author":"HJ Kim","year":"2017","unstructured":"Kim, H. J. et al. Anti-tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells. Int. J. Cancer. 140 (1), 109\u2013119 (2017).","journal-title":"Int. J. Cancer"},{"issue":"8","key":"41751_CR47","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1158\/1535-7163.MCT-18-0010","volume":"17","author":"Y Wallez","year":"2018","unstructured":"Wallez, Y. et al. The ATR inhibitor AZD6738 synergizes with gemcitabine in vitro and in vivo to induce pancreatic ductal adenocarcinoma regression. Mol. Cancer Ther. 17(8), 1670\u20131682 (2018).","journal-title":"Mol. Cancer Ther."},{"issue":"16","key":"41751_CR48","doi-asserted-by":"publisher","first-page":"1594","DOI":"10.1200\/JCO.2017.76.6915","volume":"36","author":"A Thomas","year":"2018","unstructured":"Thomas, A. et al. Phase I study of ATR inhibitor M6620 in combination with topotecan in patients with advanced solid tumors. J. Clin. Oncol. (JCO) 36(16), 1594\u20131602 (2018).","journal-title":"J. Clin. Oncol. (JCO)"},{"issue":"15","key":"41751_CR49","doi-asserted-by":"publisher","first-page":"2800","DOI":"10.1158\/1078-0432.CCR-22-2444","volume":"29","author":"S Wethington","year":"2023","unstructured":"Wethington, S. et al. C ombination A TR (ceralasertib) and P A R P (olaparib) I nhibitor (CAPRI) trial in acquired PARP inhibitor\u2013resistant homologous recombination\u2013deficient ovarian cancer. Clin. Cancer Res. 29(15), 2800\u20132807 (2023).","journal-title":"Clin. Cancer Res."},{"key":"41751_CR50","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1016\/S0959-8049(16)32607-7","volume":"69","author":"TA Yap","year":"2016","unstructured":"Yap, T. A. et al. 1LBA - Phase I modular study of AZD6738, a novel oral, potent and selective ataxia telangiectasia Rad3-related (ATR) inhibitor in combination (combo) with carboplatin, olaparib or durvalumab in patients (pts) with advanced cancers. Eur. J. Cancer. 69, S2 (2016).","journal-title":"Eur. J. Cancer"},{"issue":"15_suppl","key":"41751_CR51","doi-asserted-by":"publisher","first-page":"2504","DOI":"10.1200\/JCO.2016.34.15_suppl.2504","volume":"34","author":"B O\u2019Carrigan","year":"2016","unstructured":"O\u2019Carrigan, B. et al. 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. J. Clin. Oncol. 34 (15_suppl), 2504\u20132504 (2016).","journal-title":"J. Clin. Oncol."},{"issue":"16","key":"41751_CR52","doi-asserted-by":"publisher","first-page":"3358","DOI":"10.1158\/1078-0432.CCR-24-1047","volume":"30","author":"S Ohmura","year":"2024","unstructured":"Ohmura, S. & Gr\u00fcnewald, T. P. Optimizing ATR inhibition and cisplatin synergy in Ewing sarcoma. Clin. Cancer Res. 30(16), 3358\u20133360 (2024).","journal-title":"Clin. Cancer Res."},{"issue":"1","key":"41751_CR53","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1186\/s13018-020-02028-3","volume":"15","author":"WK Guder","year":"2020","unstructured":"Guder, W. K. et al. Pelvic Ewing sarcoma: a retrospective outcome analysis of 104 patients who underwent pelvic tumor resection at a single supra-regional center. J. Orthop. Surg, Res. 15 (1), 534 (2020).","journal-title":"J. Orthop. Surg, Res."},{"issue":"23","key":"41751_CR54","doi-asserted-by":"publisher","first-page":"5920","DOI":"10.3390\/cancers14235920","volume":"14","author":"I Kaiser","year":"2022","unstructured":"Kaiser, I. et al. Secondary malignancies after Ewing sarcoma\u2014Epidemiological and clinical analysis of an international trial registry. Cancers 14(23), 5920 (2022).","journal-title":"Cancers"},{"issue":"1","key":"41751_CR55","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1158\/1535-7163.MCT-16-0239","volume":"16","author":"M Dillon","year":"2017","unstructured":"Dillon, M. et al. Radiosensitization by the ATR inhibitor AZD6738 through generation of acentric micronuclei. Mol. Cancer Ther. 16(1), 25\u201334 (2017).","journal-title":"Mol. Cancer Ther."},{"issue":"11","key":"41751_CR56","doi-asserted-by":"publisher","first-page":"2462","DOI":"10.1158\/1535-7163.MCT-18-0470","volume":"17","author":"X Tu","year":"2018","unstructured":"Tu, X. et al. ATR inhibition is a promising radiosensitizing strategy for triple-negative breast cancer. Mol. Cancer Ther. 17(11), 2462\u20132472 (2018).","journal-title":"Mol. Cancer Ther."},{"issue":"12","key":"41751_CR57","doi-asserted-by":"publisher","first-page":"e441","DOI":"10.1038\/cddis.2012.181","volume":"3","author":"E Fokas","year":"2012","unstructured":"Fokas, E. et al. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell. Death Dis. 3(12), e441 (2012).","journal-title":"Cell. Death Dis."},{"issue":"16_suppl","key":"41751_CR58","doi-asserted-by":"publisher","first-page":"e15131","DOI":"10.1200\/JCO.2023.41.16_suppl.e15131","volume":"41","author":"M Ortiz","year":"2023","unstructured":"Ortiz, M. et al. A phase 1\/2 study of bay 18953444 (Elimusertib) in pediatric patients with relapsed or refractory solid tumors: Initial report of the phase 1 results of PEPN2112. J. Clin. Oncol. (JCO). 41 (16_suppl), e15131 (2023).","journal-title":"J. Clin. Oncol. (JCO)"},{"issue":"12_Supplement_2","key":"41751_CR59","doi-asserted-by":"publisher","first-page":"PR14","DOI":"10.1158\/1535-7163.TARG-15-PR14","volume":"14","author":"TA Yap","year":"2015","unstructured":"Yap, T. A. et al. Abstract PR14: Phase I trial of first-in-class ataxia telangiectasia-mutated and Rad3-related (ATR) inhibitor VX-970 as monotherapy (mono) or in combination with carboplatin (CP) in advanced cancer patients (pts) with preliminary evidence of target modulation and antitumor activity. Mol. Cancer Ther. 14 (12_Supplement_2), PR14\u2013PR14 (2015).","journal-title":"Mol. Cancer Ther."},{"issue":"1","key":"41751_CR60","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1158\/2159-8290.CD-20-0868","volume":"11","author":"TA Yap","year":"2021","unstructured":"Yap, T. A. et al. First-in-human trial of the oral ataxia telangiectasia and RAD3-related (ATR) inhibitor BAY 1895344 in patients with advanced solid tumors. Cancer Discov 11(1), 80\u201391 (2021).","journal-title":"Cancer Discov"},{"issue":"12_Supplement","key":"41751_CR61","doi-asserted-by":"publisher","first-page":"CT006","DOI":"10.1158\/1538-7445.AM2022-CT006","volume":"82","author":"TA Yap","year":"2022","unstructured":"Yap, T. A. et al. Abstract CT006: Phase Ib expansion trial of the safety and efficacy of the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor elimusertib in advanced solid tumors with DNA damage response (DDR) defects. Cancer Res. 82 (12_Supplement), CT006\u2013CT006 (2022).","journal-title":"Cancer Res."},{"issue":"3","key":"41751_CR62","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, N. L. & Zhang, J. ATR\/CHK1 inhibitors and cancer therapy. Radiother Oncol. 126 (3), 450\u2013464 (2018).","journal-title":"Radiother Oncol."},{"issue":"6","key":"41751_CR63","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1093\/jmcb\/mju045","volume":"6","author":"L Zannini","year":"2014","unstructured":"Zannini, L., Delia, D. & Buscemi, G. CHK2 kinase in the DNA damage response and beyond. J. Mol. Cell. Biol. 6 (6), 442\u2013457 (2014).","journal-title":"J. Mol. Cell. Biol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-41751-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-41751-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-41751-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T20:59:56Z","timestamp":1781643596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-41751-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":63,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["41751"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-41751-5","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-7879443\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]},"assertion":[{"value":"16 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10953"}}