title: Clinical and cellular roles for TDP1 and TOP1 in modulating colorectal cancer response to irinotecan.
abstract: Colorectal 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.
authors.affiliation: The Wellcome Trust DNA Repair Group, Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Meisenberg
authors.affiliation: Sussex Cancer Centre, Royal Sussex County Hospital, Brighton, United Kingdom.
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Gilbert
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Chalmers
authors.affiliation: Faculty of Science, Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes, United Kingdom.
authors.forename: Vikki
authors.initials: V
authors.lastname: Haley
authors.affiliation: North Wales Cancer Treatment Centre, Betsi Cadwaladr University of Health Board, Ysbty Glan Clwyd, Bodelwyddan, Rhyl, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Gollins
authors.affiliation: Translational Drug Discovery Group, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Ward
authors.affiliation: The Wellcome Trust DNA Repair Group, Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom. Mammalian Genome Stability Group, Krebs Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom. Center of Genomics, Helmy Institute, Zewail City of Science and Technology, Giza, Egypt. s.el-khamisy@sheffield.ac.uk.
authors.forename: Sherif F
authors.initials: SF
authors.lastname: El-Khamisy
mesh_terms: D055162:Biocatalysis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D000077146:Irinotecan; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin