However, with the current unavailability of phenformin for clinical use, it will be interesting to test MEK inhibition in combination with metformin, especially considering metformin has anti-cancer mechanisms specifically relevant to KRAS-mutant cancer, such as down-regulation of PI3K->AKT->mTOR signaling [44], displacement of constitutively active KRAS from the cell membrane and uncoupling of the MAPK signaling pathway [45]. This evidence concerns the gene AKT1 and cancer.