This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Metabolic and Molecular Mechanisms of Gemcitabine Resistance in Urothelial Carcinoma
by
, , and
Takahisa Yamashita
1
,
Shoichi Nagamoto
2,
Masahiro Arai
2,
Sachi Kitayama
2,
Akihiro Yano
2 and
Morihiro Higashi
1,* 1
Department of Pathology, Saitama Medical Center, Saitama Medical University, 1981, Kamoda, Kawagoe 350-8550, Saitama, Japan
2
Department of Urology, Saitama Medical Center, Saitama Medical University, 1981, Kamoda, Kawagoe 350-8550, Saitama, Japan
*
Author to whom correspondence should be addressed.
Cancers 2026, 18(13), 2126; https://doi.org/10.3390/cancers18132126
Submission received: 27 May 2026
/
Revised: 26 June 2026
/
Accepted: 27 June 2026
/
Published: 30 June 2026
(This article belongs to the Section Molecular Cancer Biology)
Simple Summary
Gemcitabine-based chemotherapy has long served as a standard treatment for urothelial carcinoma (UC). However, resistance to gemcitabine commonly develops in UC. Although several mechanisms of resistance have been identified in other cancers, those specific to UC have not been comprehensively summarized. This review discusses how altered drug metabolism, cellular stress responses, apoptosis regulation, and tumor microenvironmental factors collectively mediate gemcitabine resistance in UC. Rather than acting independently, these mechanisms appear to form an interconnected network that shapes treatment response. Understanding these pathways may improve future strategies for predicting treatment response and identifying therapeutic targets.
Abstract
Gemcitabine-based chemotherapy has long served as a standard treatment for urothelial carcinoma (UC), particularly in perioperative and metastatic settings. However, therapeutic efficacy is frequently limited by intrinsic or acquired resistance. Gemcitabine functions as a prodrug whose activity depends on coordinated processes involving cellular uptake, intracellular activation, metabolic inactivation, and nucleotide metabolism. Increasing evidence suggests that resistance in UC is mediated by multiple interconnected mechanisms beyond alterations in gemcitabine transport, activation, and inactivation alone. Key molecular determinants include human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), cytidine deaminase (CDA), and ribonucleotide reductase regulatory subunit M1 (RRM1), which is involved in nucleotide pool maintenance and DNA synthesis. In addition, replication stress responses, apoptosis evasion pathways, and tumor microenvironment-associated factors also contribute to gemcitabine resistance. Stress-adaptive pathways involving Y-box binding protein 1 (YB-1), hypoxia-inducible factor-1 alpha (HIF-1α), and autophagy-related mechanisms may further promote survival under chemotherapy-induced stress conditions. In addition, extracellular mucin-associated mechanisms may alter intratumoral drug accessibility and contribute to resistance. In this review, we summarize UC-specific evidence regarding gemcitabine resistance and discuss how these pathways collectively shape an integrated resistant phenotype.
