{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T22:40:44Z","timestamp":1780440044009,"version":"3.54.1"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T00:00:00Z","timestamp":1605657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970152"],"award-info":[{"award-number":["81970152"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81770177"],"award-info":[{"award-number":["81770177"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation","award":["2017CFA072"],"award-info":[{"award-number":["2017CFA072"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Deregulation of v-myc avian myelocytomatosis viral oncogene homolog (MYC) occurs in a broad range of human cancers and often predicts poor prognosis and resistance to therapy. However, directly targeting oncogenic MYC remains unsuccessful, and indirectly inhibiting MYC emerges as a promising approach. Checkpoint kinase 1 (CHK1) is a protein kinase that coordinates the G2\/M cell cycle checkpoint and protects cancer cells from excessive replicative stress. Using c-MYC-mediated T-cell acute lymphoblastic leukemia (T-acute lymphoblastic leukemia) and N-MYC-driven neuroblastoma as model systems, we reveal that both c-MYC and N-MYC directly bind to the CHK1 locus and activate its transcription. CHIR-124, a selective CHK1 inhibitor, impairs cell viability and induces remarkable synergistic lethality with mTOR inhibitor rapamycin in MYC-overexpressing cells. Mechanistically, rapamycin inactivates carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), the essential enzyme for the first three steps of de novo pyrimidine synthesis, and deteriorates CHIR-124-induced replicative stress. We further demonstrate that dual treatments impede T-acute lymphoblastic leukemia and neuroblastoma progression in vivo. These results suggest simultaneous targeting of CHK1 and mTOR as a novel and powerful co-treatment modality for MYC-mediated tumors.<\/jats:p>","DOI":"10.1093\/carcin\/bgaa119","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T12:10:17Z","timestamp":1605183017000},"page":"448-460","source":"Crossref","is-referenced-by-count":12,"title":["Synergistic targeting of CHK1 and mTOR in MYC-driven tumors"],"prefix":"10.1093","volume":"42","author":[{"given":"Xiaoxue","family":"Song","sequence":"first","affiliation":[{"name":"Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, P. R. China"},{"name":"Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, P. R. China"},{"name":"Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianci","family":"Wang","sequence":"additional","affiliation":[{"name":"Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juncheng","family":"Hu","sequence":"additional","affiliation":[{"name":"Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. 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