Non-Coding RNAs in Gastrointestinal Stromal Tumors: Regulatory Networks, Drug Resistance, and Clinical Implications

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and are usually driven by activating mutations in KIT or PDGFRA. Although these alterations define the core molecular biology of GISTs and guide targeted therapy, they do not fully explain the variability observed in tumor behavior, recurrence risk, or response to tyrosine kinase inhibitors. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been increasingly studied as regulators of gene expression in GISTs. Recent evidence suggests that these molecules may influence KIT-centered signaling, autophagy, apoptosis, invasion, angiogenesis, and drug resistance. However, the strength of evidence differs considerably across individual ncRNAs, ranging from bioinformatic associations to functional validation in cell lines and in vivo models. This review summarizes current knowledge on ncRNA-mediated regulation in GIST biology, with emphasis on tumor progression, therapeutic resistance, and possible clinical relevance. Rather than treating ncRNAs as isolated biomarkers, they function as part of broader regulatory networks that interact with oncogenic signaling and epigenetic mechanisms. Although several ncRNAs appear promising as prognostic or predictive candidates, further validation in independent clinical cohorts is required before their integration into routine risk stratification or treatment decision-making.