Clinical and cellular roles for TDP1 and TOP1 in modulating colorectal cancer response to irinotecan

Colorectal cancer (CRC) is the third most common cancer in the world. Despite surgery, up to 50% of patients relapse with incurable disease. First line chemotherapy utilises 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 CRC, 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 CRC cell lines and in clinical CRC 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 CRC. 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 CRC. These findings establish TDP1 as a potential therapeutic target for the treatment of CRC and question the validity of TOP1 or TDP1 on their own as predictive biomarkers for irinotecan response.