Portrayal of the complex molecular landscape of multidrug resistance in gastric cancer: Unveiling the potential targets

Abstract

Gastric cancer (GC) is an aggressive malignancy among all Gastrointestinal cancer (GIC) types. Worldwide, among all cancer types, gastric cancer incidence and related mortality remain in fifth position. Multidrug resistance (MDR) in GC presents a major challenge to chemotherapy, and it significantly affects patient survival. A better understanding of the dynamic interaction of cellular factors contributing to MDR phenotype, e.g., the presence and expression of variants of MDR-related genes, including various drug-detoxifying and drug-efflux transporters, and expression of regulatory ncRNAs affecting the expression of MDR-related genes, is required to comprehend the molecular mechanisms for MDR development in GCs. This review article provides a holistic discussion of the cellular factors involved in the MDR development in GC cells, i.e., their roles and cross-talk between specific molecules that give rise to drug-sensitive and drug-resistant phenotypes. Moreover, the pharmacological perspective of drug resistance and the underlying biological processes that allow the escape of GC cells from the cytotoxic effects of drugs have also been discussed. Additionally, this review article provides an in-depth discussion on most potential candidates that can serve as MDR biomarkers in GIC cancer and the growing research interest in non-coding RNAs (ncRNAs) in GC. Notably, the miRNAs, circRNAs, and lncRNAs are not only emerging as crucial prognostic biomarkers of MDR in gastric cancers but also as potential targets for personalized medicine to combat the MDR challenge in GC patients. © 2025 Elsevier Inc.