Overall, these results suggest that while some BRAF/MEK inhibitor sensitive BRAF-mutant melanomas, particularly those that express low pAKT and functional PTEN, can be effectively treated with single agent BRAF or MEK inhibition, for the majority of lines, enhancement of antitumor activity can be achieved by combining BRAF or MEK inhibition with an inhibitor of PI3K/mTOR signaling to block ERK, AKT, and S6 signaling. This evidence concerns the gene PTEN and melanoma.