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Metabolic reprogramming is as a hallmark of cancer, and several studies have reported that BRAF and KRAS tumors may be accompanied by a deregulation of cellular metabolism. We investigated how BRAF V600E  and KRAS G12V  affect cell metabolism, stress resistance and signaling in colorectal carcinoma cells driven by these mutations. KRAS G12V  expressing cells are characterized by the induction of glycolysis, accumulation of lactic acid and sensitivity to glycolytic inhibition. Notably mathematical modelling confirmed the critical role of MCT1 designating the survival of KRAS G12V  cells. Carcinoma cells harboring BRAF V600E  remain resistant towards alterations of glucose supply or application of signaling or metabolic inhibitors. Altogether these data demonstrate that an oncogene-specific decoupling of mTOR from AMPK or AKT signaling accounts for alterations of resistance mechanisms and metabolic phenotypes. Indeed the inhibition of mTOR in BRAF V600E  cells counteracts the metabolic predisposition and demonstrates mTOR as a potential target in BRAF V600E -driven colorectal carcinomas.

Alterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations