Abstract
Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is used as a first-line treatment for advanced non-small cell lung cancer (NSCLC). However, most NSCLC patients inevitably develop gefitinib resistance, and the mechanisms underlying this resistance are not fully understood. In this study, we show that miR-19a is significantly down-regulated in gefitinib-resistant NSCLC cell lines compared with gefitinib-sensitive cell lines. In addition, the down-regulation of miR-19a suppressed the expression of epithelial markers but induced the expression levels of mesenchymal markers. A mechanistic analysis revealed that miR-19a regulated c-Met expression by directly targeting the c-Met 3′UTR. Overexpression of miR-19a decreased c-Met expression and re-sensitized gefitinib-resistant NSCLC cells in vitro and in vivo. Consistent with the in vitro findings, the miR-19a serum level was significantly decreased in NSCLC patients with acquired gefitinib resistance compared with the level observed prior to the acquisition of resistance in each patient, indicating that miR-19a expression may be a valuable biomarker for the prediction of acquired gefitinib resistance in a clinical setting. Our data demonstrate that the miR-19a/c-Met pathway plays a critical role in acquired resistance to gefitinib and that the manipulation of miR-19a might provide a therapeutic strategy for overcoming acquired gefitinib resistance.
Highlights
Lung cancer is the leading cause of cancer-related mortality, accounting for nearly 1.6 million deaths per year[1]
Flamant et al reported that miR-19a is a candidate that responds to imatinib mesylate in patients with chronic myeloid leukemia (CML)[19], indicating that miR-19a may play an important role in the development of resistance to tyrosine kinase inhibitor (TKI)
Reduction of miR-19a in gefitinib-resistant non-small cell lung cancer (NSCLC) patients and cell lines. miR-19a was previously reported as a candidate that responds to imatinib mesylate in patients with CML, indicating that miR-19a may play an important role in TKI resistance[19]
Summary
Lung cancer is the leading cause of cancer-related mortality, accounting for nearly 1.6 million deaths per year[1]. Several genetic alterations in NSCLC, including KRAS gene mutations, EGFR gene mutations, and EML4-ALK rearrangements, have been identified Of these changes, EGFR gene mutations are found in approximately 10–28% of NSCLC cases and are common in women and non-smokers in the East Asian population[2]. A common tyrosine kinase inhibitor (TKI), has been approved for patients harboring exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations[5, 6]. This drug improves response rates, delays disease progression, and most importantly, increases overall survival compared with platinum-based combination chemotherapy. Our findings provide a rationale for the use of miR-19a as a predictive biomarker for gefitinib sensitivity and provide a potential therapeutic strategy for overcoming gefitinib resistance by targeting miR-19a expression
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