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

Marlies C. Ludikhuize, Sira Gevers, Nguyen T.B. Nguyen, Maaike Meerlo, S. Khadijeh Shafiei Roudbari, M. Can Gulersonmez, Edwin C.A. Stigter, Jarno Drost, Hans Clevers, Boudewijn M.T. Burgering, Maria J. Rodríguez Colman

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Samenvatting

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. Importantly, p53-deficiency leads to cell death due to impaired cell cycle arrest. Moreover, we find that targeting the Warburg effect in KRASG12D glycolytic tumor organoids enhances 5-FU toxicity by further altering the nucleotide pool and, importantly, without affecting non-transformed WT cells. Thus, p53 emerges as an important factor in determining the 5-FU response, and targeting cancer metabolism in combination with replication stress-inducing chemotherapies emerges as a promising strategy for CRC treatment.

Originele taal-2Engels
Artikelnummer1159
TijdschriftCommunications Biology
Volume5
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - dec. 2022

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