2026-10-12T16:37:50Z https://api.figshare.com/v2/oai

oai:figshare.com:article/32640924 2026-10-01T16:27:13Z portal_1172 item_type_8 month_year_10_2026

New insights into the anticancer mechanisms of combined dUTPase and thymidylate synthase inhibition in colorectal cancer Alexandra Jo Emerson (24169665) PUREID: 634112602 colorectal cancer dUTPase thymidylate synthase Colorectal cancer (CRC) represents the third leading cause of cancer, and the second leading cause of cancer-related deaths worldwide. While surgical resection remains the primary treatment for localised disease, chemotherapy is critical for advanced or metastatic CRC, where fluoropyrimidines like 5-fluorouracil (5-FU) and capecitabine form the cornerstone of standard therapeutic regimens. However, resistance to these agents a significant challenge to effect treatment, demanding novel therapeutic strategies. The enzyme deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is highly expressed in CRC and protects DNA from the genomic misincorporation of uracil (DNA uracilation) that would otherwise occur during treatment with TS inhibition. Inhibition of dUTPase has emerged as a potential strategy to enhance the cytotoxicity of TS inhibitors in cancer. However, the molecular mechanisms that underpin this DNA damage-induced cell death and the specific contribution of base excision repair (BER) remain unclear. This thesis aimed to explore the DNA damage response (DDR), the role of uracil-DNA glycosylase (UNG)-mediated BER and the immunomodulatory effects induced by DNA uracilation following combined inhibition of TS and dUTPase in CRC. The present results confirm that inhibition of dUTPase sensitises CRC cells to TS inhibition through nucleotide pool imbalances and enhanced DNA uracilation. These results additionally provide new insights into the differential consequences on DNA damage following TS inhibition alone or in combination with dUTPase inhibition, through accelerated activity of BER signalling, S-phase accumulation and increased intrinsically-mediated apoptotic cell death. Furthermore, combined inhibition of dUTPase and TS triggered unique immunomodulatory responses across transcriptional, translational, post-translational and extracellular signalling pathways. This thesis provides new insights into the synergistic and unique DNA damage and immunomodulatory mechanisms triggered by combined inhibition of dUTPase and TS in CRC. Future work is needed to validate these findings in vivo, however these insights hold significant potential for expanding therapeutic applications of dUTPase inhibitors in CRC treatment.<br><i><br>Thesis is embargoed until 31 July 2030.</i> 2026-10-01T16:27:13Z Text Thesis 10.17034/32640924.v1 https://figshare.com/articles/thesis/New_insights_into_the_anticancer_mechanisms_of_combined_dUTPase_and_thymidylate_synthase_inhibition_in_colorectal_cancer/32640924 All Rights Reserved Open Access after 2030-07-31