Metabolic reprogramming in KRAS-mutant cancers: Proven targetable vulnerabilities and potential therapeutic strategies

Kras (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), one of the most frequently mutated oncogenes in the human genome, is considered ‘untargetable’. Although specific KRAS^G12C inhibitors have been developed, their overall impact is limited, highlighting the need for further research on targeting KRAS-mutant cancers. Metabolic abnormalities are key hallmarks of cancer, with KRAS-driven tumors exhibiting traits like glycolysis upregulation, glutamine addiction, lipid droplet accumulation, highly active macropinocytosis, and metabolic reprogramming-associated tumor microenvironment remodeling. Targeting these unique metabolic characteristics offers a promising strategy for new cancer treatments. This review summarizes recent advances in our understanding of the metabolic network in KRAS-mutated tumor cells, discusses potential targetable vulnerabilities, and outlines clinical developments in relevant therapies, while also addressing challenges to improve strategies against these aggressive cancers.