Construction and validation of a gemcitabine resistance gene signature based on cholangiocarcinoma organoids

doi:10.16352/j.issn.1001-6325.2026.07.0904

Abstract

Abstract: 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 relevance. 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 resistant cells but were suppressed in sensitive cells. Conclusions This signature provides a robust and biologically interpretable indicator of GEM resistance in cholangiocarcinoma, with strong generalizability across datasets.

Key words: cholangiocarcinoma, patient-derived organoids, gemcitabine resistance, gene signature, bioinformatics analysis

CLC Number:

CHEN Ziran, HUANG Rong, LU Yan, LI Kai, SONG Wei. Construction and validation of a gemcitabine resistance gene signature based on cholangiocarcinoma organoids[J]. Basic & Clinical Medicine, 2026, 46(7): 904-912.

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