5-fluorouracil resistance pathways (5-FU resistance)

5-fluorouracil (5-FU) resistance pathways represent a multifaceted set of biological mechanisms that enable cancer cells to survive and proliferate despite treatment with the antimetabolite 5-fluorouracil [1.1.1, 1.3.1]. These pathways primarily involve the dysregulation of 5-FU metabolism, including the overexpression of its primary target, thymidylate synthase (TYMS), and the catabolic enzyme dihydropyrimidine dehydrogenase (DPYD), alongside the downregulation of activating enzymes like orotate phosphoribosyltransferase (UMPS) [1.2.1, 1.2.2]. Beyond metabolic shifts, resistance is driven by the activation of oncogenic signaling cascades such as NF-κB, Wnt/β-catenin, and PI3K/Akt, which promote cell survival and inhibit apoptosis [1.1.1, 1.3.1]. Additionally, enhanced DNA repair systems, such as mismatch repair, and increased drug efflux through ATP-binding cassette (ABC) transporters further mitigate the cytotoxic effects of 5-FU [1.4.1]. The involvement of non-coding RNAs and the epithelial-mesenchymal transition (EMT) also plays a significant role in the development of acquired resistance [1.1.3, 1.4.2]. Understanding these pathways is essential for identifying predictive biomarkers and developing synergistic drug combinations to improve clinical outcomes in patients with colorectal, gastric, and other solid tumors [1.3.4].

Other names

5-FU chemoresistanceFluorouracil resistance mechanisms5-fluorouracil resistance5-FU resistance pathways

The mechanisms of action within these pathways include the competitive inhibition of thymidylate synthase (TYMS) by the 5-FU metabolite FdUMP, which halts dTMP synthesis and DNA replication, and the misincorporation of fluorinated nucleotides into RNA and DNA [1.2.1, 1.2.4]. Resistance mechanisms counteract these actions through target amplification (TYMS), increased drug degradation (DPYD), or bypass of metabolic activation (UMPS/TYMP) [1.2.2, 1.2.3]. Furthermore, signaling pathways like NF-κB and PI3K/Akt are activated to suppress 5-FU-induced apoptosis and promote cell cycle progression [1.1.1, 1.3.1].