New insights into the anticancer mechanisms of combined dUTPase and thymidylate synthase inhibition in colorectal cancer

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>