BRAF and melanoma: Given that the MAPK and the PI3K-AKT pathways are the predominant signaling pathways in melanoma and that MAPK-independent resistance to BRAF inhibitors can be mediated through enhancement of signaling through the PI3K-AKT pathway, it would be reasonable to combine a BRAF inhibitor with an inhibitor of the PI3K-AKT pathway to achieve synergistic antitumor activity [18-22].