Given the presence of numerous inter-related treatment targets (Figure 5), simultaneous targeting of the Ras/RAF/MAPK/ERK pathway and/or the PI3K/AKT/mTOR pathway with targeted therapy such as a MEK or BRAF inhibitor in melanoma, and inhibition of the renin–angiotensin system, or direct inhibition of PRR, may result in more effective suppression of these overactive pathways. This evidence concerns the gene PIK3CA and melanoma.