We evaluated the activation of the MAPK and PI3K–Akt pathways in human BRAF V600E mutant melanoma cells (A375) transduced with a PhosphatidylInositol-4,5-bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) coding sequence that either harboured or did not harbour the H1047R mutation to establish if the PIK3CA mutation is directly involved in melanoma drug resistance and if it may represent a novel effective therapeutic target for resistant melanoma. This evidence concerns the gene PIK3CA and melanoma.