MEK inhibitors significantly enhanced antitumor efficacy in when given in combination with BRAF inhibitors for BRAF V600E mutant melanoma both in preclinical models and in clinical trials, leading to the FDA approval of dabrafenib and trametinib,43, 44, 45 as well as vemurafenib with cobimetinib.46 Further, dual pathway inhibition decreased the toxicity profile, especially by decreasing development of cutaneous malignancies.45 In contrast, dual inhibition of PI3K and mTOR with dual inhibitors has been more challenging because of the toxicity profile of these agents. The gene discussed is PIK3CA; the disease is melanoma.