634 MicroRNA-7 reverses the resistance to BRAF inhibitor in melanoma by targeting EGFR/IGF-1R/CRAF and inhibiting the MAPK and PI3K/AKT signaling pathways

Abstract

Recent breakthroughs in targeted therapies and immunotherapies have shaped the landscape of the therapeutic strategies for patients with advanced melanoma. High initial response rate and clear impact on overall survival obtained from targeted therapies (e.g., BRAF inhibitor vemurafenib and dabrafenib) are unfortunately shadowed by high rate of drug resistance. Although microRNAs (miRNAs) are attractive therapeutic targets for various therapy-resistant tumors, the association between miRNA and BRAF inhibitor resistant melanoma remains to be elucidated. Here, we used microarray analysis to comprehensively study the miRNA expression profiling of vemurafenib resistant A375 melanoma cells (VemR A375) in relation to parental A375 melanoma cells. MicroRNA-7 (miR-7) was identified to be the most significantly down-regulated miRNA in VemR A375 melanoma cells and reestablishment of miR-7 expression could reverse the resistance to vemurafenib. In addition, epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R) and CRAF have been found to be over-expressed in VemR A375 melanoma cells. Introduction of miR-7 mimics could markedly down-regulate the expressions of EGFR, IGF-1R and CRAF and further suppressed the activation of MAPK and PI3K/AKT pathway in VemR A375 melanoma cells. Furthermore, tumor growth was significantly inhibited in an in vivo murine VemR A375 melanoma tumor model transfected with miR-7 mimics. Altogether, our study provides a comprehensive validation that miR-7 reverses VemR melanoma cells to BRAF inhibitors via suppressing the over-expression of EGFR, IGF-1R and CRAF and further inhibiting the hyper-activation of the MAPK and PI3K/AKT signaling pathways. Thus, our findings suggest that miR-7 could be a potential therapeutic target for patients with BRAF inhibitor resistant melanoma.