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

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. <br><br> 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.<br><br> 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.