{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:25:24Z","timestamp":1791923124912,"version":"4.3.4"},"reference-count":50,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["GZC20240770"],"award-info":[{"award-number":["GZC20240770"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007452","name":"Wu Jieping Medical Foundation","doi-asserted-by":"publisher","award":["320.6750.2024\u201018.66"],"award-info":[{"award-number":["320.6750.2024\u201018.66"]}],"id":[{"id":"10.13039\/100007452","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2024QH181"],"award-info":[{"award-number":["ZR2024QH181"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82202848"],"award-info":[{"award-number":["82202848"]}],"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":["82372806"],"award-info":[{"award-number":["82372806"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>FBW7, a tumor suppressive E3 ubiquitin ligase frequently mutated in colorectal cancer (CRC), mediates chemotherapy resistance. While irinotecan (via its active metabolite SN38) is a first\u2010line TOP1 inhibitor for advanced CRC, the mechanistic link between FBW7 dysfunction and irinotecan resistance remains elusive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>CRISPR\/Cas9 gene editing and RNA interference were applied to establish FBW7\u2010knockout and \u2010knockdown CRC cells. CCK8 assay was performed to detect the inhibition ratio of SN38 and Maritoclax on CRC cells. Western blot, immunochemistry, RT\u2010qPCR and co\u2010immunoprecipitation were performed to detect the expression and interaction of FBW7 and MCL1. The conformational change of the FBW7 R465C mutation and its interaction with substrates were elucidated through AlphaFold. An animal experiment was performed to detect the in\u00a0vivo therapeutic effect of irinotecan and Maritoclax.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>FBW7 deficiency (including loss, low expression and mutation) reduced SN38 sensitivity and upregulated MCL1 expression in both CRC cells and patient tissues. The R465C mutation disrupted FBW7\u2010MCL1 binding and stabilized MCL1. Moreover, SN38 modulated MCL1 expression, elevated MCL1 expression led to SN38 resistance in CRC cells. Maritoclax, a specific MCL1 inhibitor, reversed irinotecan\/SN38 resistance in FBW7\u2010deficient CRC cells and xenograft models, synergizing with irinotecan to suppress tumor growth.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>FBW7 deficiency induces irinotecan resistance via MCL1 stabilization, which is therapeutically exploitable by Maritoclax. Our work identifies MCL1 inhibition as a precision strategy for FBW7\u2010deficient CRC and supports clinical translation of Maritoclax\u2010irinotecan combinations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.71419","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T11:14:56Z","timestamp":1764328496000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Maritoclax Overcomes\n                    <scp>FBW7<\/scp>\n                    Deficiency\u2010Driven Irinotecan Resistance in Colorectal Cancer by Targeting\n                    <scp>MCL1<\/scp>"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1513-6993","authenticated-orcid":false,"given":"Qian","family":"Lin","sequence":"first","affiliation":[{"name":"Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy Ocean University of China  Qingdao China"},{"name":"Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuting","family":"Liu","sequence":"additional","affiliation":[{"name":"Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongfei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology The Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Oncology The Affiliated Hospital of Qingdao University  Qingdao China"},{"name":"College of Food Science and Engineering Ocean University of China  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_12_3_1","first-page":"1537","article-title":"Colorectal Cancer Chemotherapy: The Evolution of Treatment and New Approaches","volume":"24","author":"Rachel M. 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