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

Autor: Ludikhuize MC; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG, Utrecht, the Netherlands., Gevers S; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG, Utrecht, the Netherlands., Nguyen NTB; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG, Utrecht, the Netherlands., Meerlo M; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG, Utrecht, the Netherlands., Roudbari SKS; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG, Utrecht, the Netherlands., Gulersonmez MC; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG, Utrecht, the Netherlands., Stigter ECA; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG, Utrecht, the Netherlands., Drost J; Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Clevers H; Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands.; Oncode Institute, Utrecht, The Netherlands.; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, 3584 CT, Utrecht, The Netherlands., Burgering BMT; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG, Utrecht, the Netherlands.; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, 3584 CT, Utrecht, The Netherlands., Rodríguez Colman MJ; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG, Utrecht, the Netherlands. m.j.rodriguezcolman@umcutrecht.nl.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2022 Oct 31; Vol. 5 (1), pp. 1159. Date of Electronic Publication: 2022 Oct 31.
DOI: 10.1038/s42003-022-04055-8
Abstrakt: 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 KRAS G12D 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje