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 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.