Open Access

REVIEW

Molecular Mechanisms of Gemcitabine Resistance in Cholangiocarcinoma

Sonexai Kidoikhammouan¹, Charupong Saengboonmee^2,3, Sopit Wongkham^2,3, Wunchana Seubwai^3,4,*

1 Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen, 40002, Thailand
2 Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
3 Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
4 Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

* Corresponding Author: Wunchana Seubwai. Email:

Oncology Research 2025, 33(12), 3679-3699. https://doi.org/10.32604/or.2025.069027

Received 12 June 2025; Accepted 28 September 2025; Issue published 27 November 2025

Abstract

Cholangiocarcinoma (CCA) is an aggressive cancer originating from bile duct epithelium. Surgical resection remains the primary curative treatment for CCA. However, most CCA patients are diagnosed at an advanced stage, which limits the applicability of surgical resection. Gemcitabine is widely used as a first-line chemotherapeutic agent for unresectable CCA. Its efficacy is often compromised by the development of drug resistance, which leads to poor clinical outcomes and low survival rates of CCA patients. At present, the mechanisms underlying gemcitabine resistance in CCA remain unclear. This review aimed to comprehensively summarize the current knowledge on the molecular mechanisms underlying gemcitabine resistance in CCA and highlight emerging therapeutic strategies that may overcome this resistance. Gemcitabine resistance arises through multiple mechanisms, including reduced drug uptake and increased efflux, impaired drug activation, enhanced DNA repair, apoptosis evasion, aberrations in cell-cycle progression, induction of epithelial–mesenchymal transition, metabolic reprogramming, alteration of tumor, and activation of oncogenic pathways contributes to gemcitabine resistance. A deeper understanding of gemcitabine resistance mechanisms highlights the need for combining gemcitabine with pathway-specific inhibitors, which hold promise for overcoming resistance and improving patient outcomes.

---

Keywords

---