{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:24:01Z","timestamp":1787217841977,"version":"build-2736575974"},"reference-count":65,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["263978"],"award-info":[{"award-number":["263978"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"award":["263978"],"award-info":[{"award-number":["263978"]}],"id":[{"id":"https:\/\/ror.org\/01gavpb45","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010785","name":"Foundational Projects Operating Grant Program D2R","doi-asserted-by":"publisher","award":["FDN2-A2-105"],"award-info":[{"award-number":["FDN2-A2-105"]}],"id":[{"id":"10.13039\/501100010785","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Metastatic colorectal cancer (mCRC) remains difficult to treat, largely due to chemotherapy resistance. Mutations in TP53 impair apoptosis and are associated with poor response to irinotecan. This study aimed to determine whether targeting Survivin, a key inhibitor of apoptosis, and using the disulfiram-derived compound CuET could restore apoptotic signaling and improve irinotecan efficacy. Methods: Human CRC cell lines with varying TP53 status and murine tumor models were treated with irinotecan (or its active metabolite SN-38), the Survivin inhibitor YM-155, and CuET, alone or in combination. Cell viability, clonogenic survival, and apoptotic signaling were assessed using cytotoxicity assays, flow cytometry, confocal microscopy, and Western blotting. In vivo efficacy was evaluated in xenograft and syngeneic mouse models through tumor growth measurements and histological analyses. Results: Inhibition of Survivin with YM-155 enhanced irinotecan-induced cytotoxicity and promoted caspase-dependent apoptosis in CRC cells. Irinotecan treatment induced Survivin expression, suggesting an adaptive resistance mechanism that was reversed by YM-155. CuET demonstrated potent cytotoxic activity independent of TP53 status and partially suppressed Survivin expression. Importantly, CuET restored sensitivity to irinotecan in TP53-deficient models and significantly enhanced antitumor efficacy in vivo, leading to reduced tumor growth, decreased proliferation, and increased apoptosis. Conclusions: These findings identify Survivin-mediated apoptotic resistance as a key determinant of irinotecan response in CRC. Targeting this pathway, either directly through Survivin inhibition or through CuET-induced stress responses, restores apoptotic sensitivity and enhances chemotherapy efficacy. This study supports the development of combination strategies incorporating CuET to overcome resistance in TP53-mutant CRC.<\/jats:p>","DOI":"10.3390\/cancers18162687","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T11:04:12Z","timestamp":1787137452000},"page":"2687","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Overcoming Resistance: Targeting Survivin-Driven Apoptotic Resistance Restores Irinotecan Sensitivity in TP53-Mutant Colorectal Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1670-6633","authenticated-orcid":false,"given":"Daciana Catalina","family":"Dumut","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC H3A 1Y2, Canada"},{"name":"Infectious Diseases in Global Health Program, The Research Institute of the McGill University Health Centre, Montreal, QC H3A 1A1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Zhong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC H3A 1Y2, Canada"},{"name":"Infectious Diseases in Global Health Program, The Research Institute of the McGill University Health Centre, Montreal, QC H3A 1A1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Verelli","sequence":"additional","affiliation":[{"name":"Infectious Diseases in Global Health Program, The Research Institute of the McGill University Health Centre, Montreal, QC H3A 1A1, Canada"},{"name":"Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montreal, QC H3A 0G4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viswanath","family":"Das","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic"},{"name":"Czech Advanced Technology and Research Institute, Palacky University Olomouc, Krizkovskeho 511\/8, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4834-908X","authenticated-orcid":false,"given":"Marian","family":"Hajduch","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic"},{"name":"Czech Advanced Technology and Research Institute, Palacky University Olomouc, Krizkovskeho 511\/8, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5480-4608","authenticated-orcid":false,"given":"Juan Bautista","family":"De Sanctis","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic"},{"name":"Czech Advanced Technology and Research Institute, Palacky University Olomouc, Krizkovskeho 511\/8, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danuta","family":"Radzioch","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC H3A 1Y2, Canada"},{"name":"Infectious Diseases in Global Health Program, The Research Institute of the McGill University Health Centre, Montreal, QC H3A 1A1, Canada"},{"name":"Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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