Targeting STAT3 restores BRAF inhibitor sensitivity through miR-759-3p in human cutaneous melanoma cells

Melanoma treatment with the BRAF V600E inhibitor vemurafenib provides therapeutic benefits, but the common emergence of drug resistance remains a challenge. To define molecular mechanisms of vemurafenib resistance, we generated A375-R, WM35-R cell lines resistant to vemurafenib and found that the p-STAT3 was upregulated in these cells in vitro and in vivo. In particular, activation of the STAT3 pathway was associated with vemurafenib resistance. Inhibition of this pathway with STAT3-specific siRNA (shRNA) sensitized A375-R, WM35-R cells to vemurafenib and induced apoptosis in vitro and in vivo. Moreover, targeting STAT3 induced expression of miR-579-3p and elicited resistance to vemurafenib. However, targeting miR-579-3p with anti- miR-579-3p reversed the resistance to vemurafenib. Together, these results indicate that STAT3-mediated downexpression of miR-579-3p caused resistance to vemurafenib. Our findings suggest novel approaches to overcome resistance to vemurafenib by combining vemurafenib with STAT3 silencing or miR-579-3p overexpression.