Implications of MicroRNAs in the Treatment of Gefitinib-Resistant Non-Small Cell Lung Cancer

Abstract

Non-small cell lung cancer (NSCLC) represents about 85% of the reported cases of lung cancer. Acquired resistance to targeted therapy with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is not uncommon. It is thus vital to explore novel strategies to restore sensitivity to gefitinib. Provided that microRNAs (miRNAs) negatively regulate their gene targets at the transcriptional level, it is speculated that miRNA mimetics may reduce the expression, activity and signal transduction of EGFR so that sensitization of tumour sites to gefitinib-induced cytotoxicity can be achieved. Indeed, a growing body of evidence has shown that the manipulation of endogenous levels of miRNA not only attenuates the EGFR/PI3K/Akt phosphorylation cascade, but also restores apoptotic cell death in in vitro models of experimentally-induced gefitinib resistance and provoked tumour regression/shrinkage in xenograft models. These data are in concordant with the clinical data showing that the differential expression profiles of miRNA in tumour tissues and blood associate strongly with drug response and overall survival. Furthermore, another line of studies indicate that the chemopreventive effects of a variety of natural compounds may involve miRNAs. The present review aims to discuss the therapeutic capacity of miRNAs in relation to recent discoveries on EGFR-TKI resistance, including chronic drug exposure and mutations.

miR-184 Inhibits Tumor Invasion, Migration and Metastasis in Nasopharyngeal Carcinoma by Targeting Notch2

“…MicroRNAs (miRNAs) are a class of endogenous short non-coding RNAs, which can repress gene expression by base pairing to specific recognition sequences in the 3′-untranslated region (UTR) of their target mRNAs [4]. Accumulating evidence has shown that miRNAs are associated with tumourigenesis, progression and metastasis either as oncogenes or tumour suppressors in NPC and other cancers by regulating target gene expression [5][6][7].…”

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

“…However, the relatively rapid acquisition of resistance to such treatments that is observed in virtually all patients significantly limits their utility and remains a substantial challenge to the clinical management of advanced lung cancers and the further development of targeted therapies. Since molecular mechanisms of resistance have been identified, new strategies to overcome or prevent the development of resistance have emerged, including the regulation of specific signalling pathways by epigenetic mechanisms [9].…”

Over-regulation of microRNA-133b inhibits cell proliferation of cisplatin-induced non-small cell lung cancer cells through PI3K/Akt and JAK2/STAT3 signaling pathway by targeting EGFR

“…Thus, this may affect the regulation of the proliferation, apoptosis as well as invasion of tumor cells and other important physiological activities (26). To be specific, the upregulation of PI3K/ AKT/mTOR pathway can promote the proliferation of tumor cells, induce the invasiveness and inhibit apoptosis of tumor cells, and promote tumor growth (27). Therefore, a variety of PI3K/AKT/mTOR pathway inhibitors have been developed.…”