In vitro melanoma cell lines with acquired resistance to BRAF/MEKi showed upregulation of miR-99b~125a~let-7e cluster and SPACA6 compared to their sensitive counterparts, and the concomitant inhibition of miR-99b, miR-125a, and let-7e increased cell sensitivity to BRAFi, demonstrating their direct involvement in drug resistance. This evidence concerns the gene BRAF and melanoma.