Identification of mitochondrial metabolism as a driver of chemotherapy resistance in colorectal cancer

  • Debbie Moss

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Colorectal cancer (CRC) is the second most lethal cancer worldwide and treatment options remain limited for these patients. The backbone of chemotherapy is 5-Fluorouracil (5FU), but only 10-15% of patients respond and whilst this rises to 40-50% when used in combination with other chemotherapies, drug resistance remains a major obstacle in the treatment of CRC. Therefore, a better understanding of the mechanisms driving 5FU resistance in CRC is vital.

 Metabolic reprogramming is now an accepted ‘Hallmark of Cancer’ and more recently has been shown to alter therapeutic susceptibility. Altered metabolic programs have been reported for CRC, but the importance of this in contributing to therapy resistance remains unclear. Our hypothesis was that specific metabolic programs could be mediating response to 5FU in CRC and a more in-depth understanding of the metabolic impact of 5FU may help us predict 5FU resistance clinically.

 Using a multi-omics approach we mapped response to 5FU-based treatments in human and murine CRC models and uncovered a significant role for mitochondrial metabolism in mediating 5FU response and that this promotes cell survival. We also found that this metabolic reprogramming drove acquired 5FU resistance and was predictive of intrinsic resistance in CRC patients. Finally, this resulted in a 5FU-imposed metabolic dependency that can be targeted therapeutically to improve responses across in vitro and in vivo models.

Thesis embargoed until 31st July 2028
Date of AwardJul 2023
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsDepartment for Education & Cancer Research UK
SupervisorIan Mills (Supervisor), Melissa LaBonte Wilson (Supervisor) & Emma Kerr (Supervisor)

Keywords

  • Cancer metabolism
  • drug resistance
  • 5-Fluorouracil
  • Colorectal Cancer

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