Fig. 7
Mechanistic features of synergy between IACS and STN. IACS treatment inhibits mitochondrial complex I and ATP generation by the electron transport chain (ETC), resulting in activation of AMPK, inhibition of mTOR, MAPK, and FA synthesis. IACS treatment also decreases acetyl CoA (Ac-CoA) uptake into FA synthesis, but increases its uptake into HMGCoA synthesis and activates mevalonate (MEV) pathway. This in turn activates RAS-mediated AKT. STN inhibits HMGCR, resulting in the inhibition of MEV pathway and AKT. Combination of IACS with STN starves inhibits FA-dependent BRAFV600E mutant melanoma cells by inhibition of FA and MEV pathways as well as MAPK and AKT pro-survival pathways