Glutathione metabolism–associated resistance to cisplatin and 5-FU in esophageal cancer: a paired transcriptomic study

BACKGROUND: Cisplatin plus 5-fluorouracil (CF) remains a cornerstone of treatment for locally-advanced esophageal cancer (EC). However, resistance to CF-based neoadjuvant chemotherapy (NAC) remains a major clinical challenge. Clarifying whether resistance-associated molecular features are induced by treatment or already present before therapy is crucial for improving patient stratification. METHODS: RNA sequencing was performed on paired tumor specimens from patients with EC treated with CF-based NAC, including pre-treatment biopsies (PreNAC) and post-treatment surgical samples (PostNAC) (n = 15; recurrence, n = 7; non-recurrence, n = 8). Differential gene expression analysis was conducted across four groups defined by sample timing (Pre vs. PostNAC) and recurrence status. RESULTS: PostNAC transcriptional changes in recurrent tumors were relatively limited, with only 53 genes upregulated and 54 genes downregulated compared with PreNAC samples. Notably, genes involved in glutathione metabolism emerged as the dominant resistance-associated pathway and were consistently enriched in recurrent tumors at both PreNAC and PostNAC stages. Key glutathione-related genes, including GSTP1 and GPX2, were highly expressed in recurrent cases, indicating that major resistance-associated molecular features are often already established prior to chemotherapy rather than being newly acquired during NAC. CONCLUSIONS: Our findings suggest that the molecular characteristics associated with CF resistance are frequently present before the initiation of chemotherapy. These results highlight the clinical potential of pretreatment molecular profiling as a strategy to guide therapeutic decision-making and optimize CF-based NAC in EC.