Abstract
Non-small cell lung cancer (NSCLC) harboring activating mutations in the Epidermal Growth Factor Receptor (EGFR) has been effectively treated with EGFR tyrosine kinase inhibitors (TKIs). However, the clinical efficacy of these targeted therapies is invariably limited by the development of acquired resistance. While secondary mutations like T790M and bypass pathway activation are well-documented mechanisms, there is a growing appreciation for the profound role of epigenetic regulators, particularly microRNAs (miRNAs), in orchestrating the resistant phenotype. This review provides a comprehensive and detailed analysis of the multifaceted roles of miRNAs in the emergence and maintenance of EGFR-TKI resistance in NSCLC, including their regulation of alternative receptor tyrosine kinase signaling pathways, driving phenotypic plasticity, specifically the epithelial-mesenchymal transition (EMT) and the acquisition of cancer stem cell (CSC) characteristics, as well as dysregulating core cellular processes, such as apoptosis. We further examine the complex interplay within competing endogenous RNA (ceRNA) networks, where long non-coding RNAs and circular RNAs sequester miRNAs, thereby modulating the expression of resistance-associated genes. Finally, the potential of specific miRNAs as circulating biomarkers for monitoring treatment response and as therapeutic targets to overcome resistance is discussed. This review underscores the central role of miRNA-mediated gene regulation as a critical layer of complexity in EGFR-TKI resistance, highlighting a sophisticated network that governs the fate of cancer cells under therapeutic pressure.