Assessment of the mechanism(s) involved in the enhanced anti-melanoma efficacy by co-targeting of MEK1/2 and PI3K/mTOR, compared to mutant BRAF and PI3K/mTOR dual inhibition, provided evidence for a more effective induction of apoptosis, not only in-vitro, but also in-vivo and even in cross-resistant cell lines. This evidence concerns the gene MAP2K1 and melanoma.