Molecular mechanisms underlying the role of microRNAs in resistance to epidermal growth factor receptor-targeted agents and novel therapeutic strategies for treatment of non-small-cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the deadliest types of cancer. One explanation for this poor prognosis is the failure of most chemotherapeutic regimens, which prompted the development of new, rationally designed, targeted antitumor agents, such as inhibitors of the epidermal growth factor receptor (EGFR) and downstream pathways. However, most of these targeted therapies also fail, and studies on the mechanisms underlying resistance toward targeted agents might provide critical findings for NSCLC research and treatment. Some of these studies showed that drug resistance can emerge not only from genetic aberrations, but also from epigenetic changes, including regulation of different signaling pathways by microRNAs (miRNAs), which act as key post-transcriptional regulators of gene expression. There is accumulating evidence that specific miRNAs correlated with drug sensitivity and can be used as prognostic markers in NSCLC. However, a greater knowledge of miRNAs might also provide novel insights in several drug-resistance mechanisms; hence, suggesting their potential in novel therapeutic interventions, by sensitizing tumor cells to drug-induced apoptosis as well as by inhibiting tumor proliferation and invasive capabilities. Therefore, this review highlights several recent and clinically relevant aspects of the regulation of drug resistance by miRNAs from the perspective of current anti-EGFR-targeted therapies in NSCLC.