PRPS1 and neoplasm: Here, we showed that accumulation of intracellular PRPP, produced by consistently active relapse‐specific PRPS1 mutants, could promote 5‐FU prodrug activation and confers much more sensitivity to 5‐FU on PRPS1 mutant Reh cells, prompting that both the mutations in PRPS1 and the expression of PRPS1 are potential biomarkers that can be used to predict tumor sensitivity to 5‐FU.