Rewiring glucose metabolism improves 5-FU efficacy in p53-deficient/KRAS^G12D glycolytic colorectal tumors.

ABSTRACT: Despite the fact that 5-fluorouracil (5-FU) is the backbone for chemotherapy in colorectal cancer (CRC), the response rates in patients is limited to 50%. The mechanisms underlying 5-FU toxicity are debated, limiting the development of strategies to improve its efficacy. How fundamental aspects of cancer, such as driver mutations and phenotypic heterogeneity, relate to the 5-FU response remains obscure. This largely relies on the limited number of studies performed in pre-clinical models able to recapitulate the key features of CRC. Here, we analyzed the 5-FU response in patient-derived organoids that reproduce the different stages of CRC. We find that 5-FU induces pyrimidine imbalance, which leads to DNA damage and cell death in the actively proliferating cancer cells deficient in p53. Im

SUBMITTER: Ludikhuize MC 

PROVIDER: S-EPMC9622833 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature