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

Sci Signal. 2022 Oct 18;15(756):eabj3490. doi: 10.1126/scisignal.abj3490. Epub 2022 Oct 18.


Mutations in guanosine triphosphatase KRAS are common in lung, colorectal, and pancreatic cancers. The constitutive 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.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Guanosine
  • Humans
  • Mutation
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / metabolism
  • Proto-Oncogene Proteins p21(ras)* / genetics
  • Proto-Oncogene Proteins p21(ras)* / metabolism
  • Signal Transduction
  • Tumor Microenvironment / genetics


  • Proto-Oncogene Proteins p21(ras)
  • Guanosine
  • KRAS protein, human