Plasma microRNA alterations between EGFR-activating mutational NSCLC patients with and without primary resistance to TKI

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have obtained excellent therapeutic effects against non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. However, some patients have exhibited primary resistance which becomes a major obstacle in effective treatment of NSCLC. The mechanisms of EGFR-TKIs resistance involved are still poorly understood. Many studies suggest that miRNAs play an important role in regulating drug sensitivity of EGFR-TKIs. The aim of the present study was to examine differentially expressed miRNAs in plasma between EGFR-TKIs sensitive and EGFR-TKIs primary resistance patients. MiRNA microarray of plasma from patients’ blood identified 16 differentially expressed miRNAs of which 15 (hsv2-miR-H19, hsa-miR-744-5p, hsa-miR-3196, hsa-miR-3153, hsa-miR-4791, hsa-miR-4803, hsa-miR-4796-3p, hsa-miR-372-5p, hsa-miR-138-2-3p, hsa-miR-16-1-3p, hsa-miR-1469, hsa-miR-585-3p, ebv-miR-BART14-5p, hsa-miR-769-3p, hsa-miR-548aq-5p) were down regulated while only hsa-miR-503-3p was up regulated in primary resistant patients’ plasma. Volcano plot and hierarchical clustering were performed to examine the accuracy of the miRNAs. Then validation with quantitative real-time PCR was performed and the result was in accordance with the array data. Functional analysis of these differentially expressed miRNAs with Ingenuity Pathway Analysis (IPA) revealed a common signaling network including MYC, CCND1, IGF1 and RELA. In conclusion, our finding may play important role in understanding the mechanisms underlying the problem and should be further evaluated as potential biomarkers in primary resistance of NSCLC.