Abstract
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) ranks among the deadliest cancers globally. Despite gemcitabine being a primary chemotherapeutic agent, many patients with PDAC develop resistance, significantly limiting treatment efficacy. This study aims to screen and validate key genes associated with gemcitabine resistance in advanced PDAC using bioinformatics analysis and clinical sample validation, thereby providing potential noninvasive biomarkers and therapeutic targets for overcoming chemoresistance. METHODS: This study used bioinformatics approaches to analyze gene expression data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, identifying differentially expressed genes (DEGs) associated with gemcitabine resistance in advanced PDAC. A total of 122 patients with advanced PDAC were selected for the study and divided into gemcitabine-sensitive and gemcitabine-resistant groups post-treatment. The expression levels of key genes in patients' serum were measured using enzyme-linked immunosorbent assay, and both univariate and multivariate analyses were performed to assess their potential as noninvasive biomarkers for predicting resistance. RESULTS: Ten upregulated DEGs related to gemcitabine resistance were identified. Among these genes, cathepsin E (CTSE) was significantly negatively correlated with overall survival, disease-specific survival, and progression-free interval in patients with PDAC and was thus identified as a significant key gene. Further clinical sample validation confirmed that CTSE expression level was significantly higher in the resistant group of patients with advanced PDAC compared to the sensitive group, establishing CTSE as an independent predictor of gemcitabine resistance. CONCLUSIONS: CTSE is a key gene associated with gemcitabine resistance in advanced PDAC and shows promise as a target for enhancing responsiveness to gemcitabine treatment.