Identification of novel treatment approaches for poor prognostic <i>BRAF</i>MT colorectal cancer

Novel UPR agonist compound BOLD-100 testing using cell line models revealed <i>BRAF</i>MT-specific activation of UPR and induction of DNA damage, validated at both transcriptional and translational levels. Combining BOLD-100 with an ATR inhibitor displayed synergy in a panel of <i>BRAF</i>MT CRC cell lines. Further analysis showed BOLD-100 induced DNA damage was moderated by increasing intracellular ROS.

Additionally, a novel mechanism of BOLD-100 action was discovered, involving the AhR-CYP1A1 pathway axis. Furthermore, high DDR pathway expression was identified as a predictive biomarker for adjuvant chemotherapy benefit in CRC stage III patients.<br><br>In summary, this study uncovers unique CMS1<i> BRAF</i>MT CRC biology characterised by increased UPR and DDR pathway gene expression. It introduces the novel compound BOLD-100 as a promising UPR agonist inducing DNA damage in a <i>BRAF</i>MT-specific manner.

These findings highlight the importance of UPR and DDR pathways in regulating <i>BRAF</i>MT CRC cell survival. The study supports further investigation into BOLD-100 in combination with ATR inhibitors for treatment of <i>BRAF</i>MT CRC tumours.<br><br><i>Thesis is embargoed until 31 December 2028</i>.<br><br><br>