Thus, Vav1-driven BRAFi/MEKi resistance appears highly resilient to genetic depletion and pharmacological inhibition of MEK1/2, which suggested that (i) alternative signaling pathways might be upregulated to promote the Rac1-dependent BRAFi/MEKi resistance of Vav1-overexpressing melanoma cells, and (ii) such compensatory mechanisms might be even more highly active when MEK1/2 are genetically depleted by RNAi. This evidence concerns the gene RAC1 and melanoma.