Identification of novel treatment approaches for poor prognostic BRAFMT colorectal cancer

  • Daryl James Griffin

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Colorectal cancer (CRC) ranks third globally in cancer incidence, accounting for over 1.9 million cases and 930,000 deaths in 2020, contributing to 15% of cancer-related fatalities. Early-stage CRC has a favourable 90% 5-year survival rate, but metastatic colorectal cancer (mCRC) drops survival to a bleak 10%. Among mCRC cases, 8-12% harbour BRAF mutations, particularly V600E, associated with poor responses to standard chemotherapies. First-line treatment typically involves doublet chemotherapy (FOLFOX/XELOX/CAPOX or FOLFIRI/XELIRI). Second/third-line therapy combines EGFR and BRAF inhibition (Cetuximab and Encorafenib), although resistance remains a clinical challenge. This study addresses the unmet need for disseminating BRAFMT V600E CRC biology and identifying novel therapeutic targets.

Transcriptomic analysis of CRC cell lines and clinical datasets uncovered a distinct consensus molecular subtype 1 (CMS1) BRAFMT biology characterised by increased unfolded protein response (UPR) and DNA damage repair (DDR) pathway expression. Novel UPR agonist compound BOLD-100 testing using cell line models revealed BRAFMT-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 BRAFMT 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.

In summary, this study uncovers unique CMS1 BRAFMT 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 BRAFMT-specific manner. These findings highlight the importance of UPR and DDR pathways in regulating BRAFMT CRC cell survival. The study supports further investigation into BOLD-100 in combination with ATR inhibitors for treatment of BRAFMT CRC tumours.

Thesis is embargoed until 31 December 2028.


Date of AwardDec 2023
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsNorthern Ireland Department for the Economy, Bold Therapeutics Inc, Merck KGaA & Oncoceutics, Inc
SupervisorSandra Van Schaeybroeck (Supervisor) & Simon McDade (Supervisor)

Keywords

  • BRAF
  • colorectal cancer
  • DNA damage repair
  • unfolded protein response
  • AhR
  • CYP1A1

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