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Clinical and cellular roles for TDP1 and TOP1 in modulating colorectal cancer response to irinotecan.
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posted on 2023-06-08, 19:56 authored by Cornelia Meisenberg, Duncan C Gilbert, Anthony Chalmers, Vikki Haley, Simon Gollins, Simon E Ward, Sherif F El-KhamisyColorectal cancer is the third most common cancer in the world. Despite surgery, up to 50% of patients relapse with incurable disease. First-line chemotherapy uses the topoisomerase 1 (TOP1) poison irinotecan, which triggers cell death by trapping TOP1 on DNA. The removal of TOP1 peptide from TOP1-DNA breaks is conducted by tyrosyl-DNA phosphodiesterase 1 (TDP1). Despite putative roles for TDP1 and TOP1 in colorectal cancer, their role in cellular and clinical responses to TOP1-targeting therapies remains unclear. Here, we show varying expression levels of TOP1 and TDP1 polypeptides in multiple colorectal cancer cell lines and in clinical colorectal cancer samples. TDP1 overexpression or TOP1 depletion is protective. Conversely, TDP1 depletion increases DNA-strand breakage and hypersensitivity to irinotecan in a TOP1-dependent manner, presenting a potential therapeutic opportunity in colorectal cancer. TDP1 protein levels correlate well with mRNA and with TDP1 catalytic activity. However, no correlation is observed between inherent TDP1 or TOP1 levels alone and irinotecan sensitivity, pointing at their limited utility as predictive biomarkers in colorectal cancer. These findings establish TDP1 as a potential therapeutic target for the treatment of colorectal cancer and question the validity of TOP1 or TDP1 on their own as predictive biomarkers for irinotecan response. Mol Cancer Ther; 14(2); 1-11. ©2014 AACR.
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Publication status
- Published
Journal
Molecular Cancer TherapeuticsISSN
1535-7163Publisher
American Association for Cancer ResearchExternal DOI
Issue
2Volume
14Page range
1-11Department affiliated with
- Chemistry Publications
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- No
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- Yes
Legacy Posted Date
2015-02-04Usage metrics
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