FIGURE 4.

RAS mutations rewire tumor metabolism. RAS‐induced metabolic reprogramming involving enhanced glycolysis, glutaminolysis, autophagy and macropinocytosis supports the tumor proliferation and survival. Mutated RAS dysregulates tumor metabolism by enhancing the expression of transporters and rate‐limiting enzymes of both glucose and glutamine metabolism. The intermediates of glycolysis and glutaminolysis fuel the TCA cycle that provides materials for the biosynthesis of lipids and nucleotides, as well as the production of ATP through oxidative phosphorylation. Glutamine metabolism is critical in maintaining redox homeostasis, as it acts as nitrogen donor and provides NADPH for the production of GSH. Besides, oncogenic RAS activates NRF2 to transcriptionally modulates redox balance of tumor. RAS‐mutated tumor cells exhibit elevated levels of autophagy and macropinocytosis, which digest extra‐ and intra‐cellular macromolecules into free nutrients to support survival and proliferation under nutrient‐depleting condition. Abbreviations: HK1, hexokinase 1; HK2, hexokinase 2; G‐6‐P, glucose 6‐phosphate; F‐6‐P, fructose 6‐phosphate, F‐1,6‐BP, fructose 1,6‐bisphosphate; G‐3‐P, glyceraldehyde 3‐phosphate; G‐1,3‐BP, glycerate 1,3‐bisphosphate; PFK1, phosphofructokinase‐1, GAPDH, glyceraldehyde 3‐phosphate dehydrogenase; LDHA1, lactate dehydrogenase A1; SLC, solute carrier; GLUT, glucose transporter; GOT, glutamate oxaloacetate transaminase; GLS, glutaminase; GLUD, glutamate dehydrogenase; α‐KG, α‐ketoglutarate; TCA, tricarboxylic; GSH, glutathione; GSSG, glutathione disulfide; ME1, malic enzyme 1; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; NADH, nicotinamide adenine dinucleotide hydrogen; NRF2, nuclear factor erythroid 2‐related factor 2