基于胆管癌类器官的吉西他滨耐药基因特征构建与验证OA

Objective To develop a transcriptional signature of gemcitabine(GEM)resistance using patient-derived organoids(PDOs)from cholangiocarcinoma and to validate its biological consistency and predictive rele-vance.Methods Transcriptomic profiles and drug sensitivity data from four PDOs were collected and analyzed through Hallmark pathway enrichment and pre-ranked GSEA in order to construct a 23-gene resistance signature.The associated pathway patterns were validated in TCGA-CHOL and GSE236894 cohorts,while correlations with drug response metrics were assessed with CCLE and PharmacoDB,complemented by experimental validation in cell models.Results GEM resistance was primarily enriched in cell cycle and E2F target pathways.The 23-gene signature was positively correlated with AUC in PDOs and significantly associated with proliferation markers(e.g.,TOP2A,MKI67)and cell cycle activity in independent cohorts.Database analyses further demonstrated a significant positive correlation between the signature score and GEM AAC_recomputed(ρ=0.149,P＜0.001),with higher scores which indicated a stronger resistance.Experimental findings confirmed that signature-related genes remained expressed in re-sistant cells but were suppressed in sensitive cells.Conclusions This signature provides a robust and biologically in-terpretable indicator of GEM resistance in cholangiocarcinoma,with strong generalizability across datasets.