Rerouting the drug response: Overcoming metabolic adaptation in KRAS-mutant cancers

Mutations in guanosine triphosphatase KRAS are common in lung, colorectal, and pancreatic cancers. The con-stitutive activity of mutant KRAS and its downstream signaling pathways induces metabolic rewiring in tumor cells that can promote resistance to existing therapeutics. In this review, we discuss the metabolic pathways that are altered in response to treatment and those that can, in turn, alter treatment efficacy, as well as the role of metabolism in the tumor microenvironment (TME) in dictating the therapeutic response in KRAS-driven cancers. We highlight metabolic targets that may provide clinical opportunities to overcome therapeutic resistance and improve survival in patients with these aggressive cancers.