The introduction of EGFR-tyrosine kinase inhibitors (TKIs) has revolutionized the treatment and prognosis of non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations. However, these patients display disease progression driven by the onset of acquired mechanisms of drug resistance that limit the efficacy of EGFR-TKI to no longer than one year. Moreover, a small fraction of EGFR-mutated NSCLC patients does not benefit from this targeted treatment due to primary (i.e. intrinsic) mechanisms of resistance that preexist prior to TKI drug treatment. Research efforts are focusing on deciphering the distinct molecular mechanisms underlying drug resistance, which should prompt the development of novel antitumor agents that surmount such chemoresistance modalities.

The capability of microRNAs (miRNAs) to regulate the expression of many oncogenic pathways and their central role in lung cancer progression, provided new directions for research on prognostic biomarkers, as well as innovative tools for predicting patients’ response to systemic therapies. Recent evidence suggests that modulation of key miRNAs may also reverse oncogenic signaling pathways, and potentiate the cytotoxic effect of anti-cancer therapies.

In this review, we focus on the putative emerging role of miRNAs in modulating drug resistance to EGFR-TKI treatment in EGFR-mutated NSCLC. Moreover, we discuss the current implications of miRNAs analyses in the clinical setting, using both tissue and liquid biopsies, as well as the future potential use of miRNA-based therapies in overcoming resistance to targeted agents like TKIs.