Oncogenic mutations in KRAS drive common metabolic programmes that facilitate tumour survival, growth and immune evasion in colorectal carcinoma, non-small-cell lung cancer and pancreatic ductal adenocarcinoma. However, the impacts of mutant KRAS signalling on malignant cell programmes and tumour properties are also dictated by tumour suppressor losses and physiological features specific to the cell and tissue of origin. Here we review convergent and disparate metabolic networks regulated by oncogenic mutant KRAS in colon, lung and pancreas tumours, with an emphasis on co-occurring mutations and the role of the tumour microenvironment. Furthermore, we explore how these networks can be exploited for therapeutic gain.
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S.A.K. is supported by NIH award F31CA247457. T.P. is supported by NIH grants R37CA222504 and R01CA227649 and American Cancer Society Research Scholar Grant RSG-17-200-01—TBE. Y.M.S. is supported by NIH grants R01CA245546 and R01CA148828. C.A.L. is supported by NIH grants R37CA237421, R01CA248160 and R01CA244931.
T.P. has received honoraria and consulting fees from Calithera Biosciences and research support from Dracen Pharmaceuticals and Agios Pharmaceuticals. C.A.L. has received consulting fees from Astellas Pharmaceuticals and is an inventor on patents pertaining to KRAS-regulated metabolic pathways, redox control pathways in pancreatic cancer and targeting the GOT1 pathway as a therapeutic approach. Y.M.S. and S.A.K. have no competing interests to declare.
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The enzymatic oxidation of glucose to pyruvate, which produces energy and carbon for bioenergetic and biosynthetic processes.
- Oxidation state
In cellular metabolism, the availability of electron acceptors as determined by the breakdown or production of metabolites.
Selective targeting and degradation of mitochondria, often those that are defective or excessive.
- Electron transport chain
(ETC). A series of electron-accepting enzymes embedded in the inner mitochondrial membrane responsible for producing the proton-motive force needed for energy production.
- Reactive oxygen species
(ROS). Small, oxygen-containing molecules that are highly reactive due to the electron-accepting nature of oxygen.
- Mitochondrial fission or mitochondrial fusion
A process by which mitochondria are combined (fusion) or divided into smaller fragments (fission).
The enzymatic breakdown of the amino acid glutamine.
- Tricarboxylic acid (TCA) cycle
A series of mitochondrial enzymatic reactions that oxidize metabolic intermediates to produce reducing equivalents that drive the electron transport chain and intermediates for the synthesis of lipids and amino acids.
Replenishment of tricarboxylic acid cycle intermediates.
Regulated, non-specific engulfment of the extracellular space by the cellular plasma membrane to obtain nutrients.
Degradation of intracellular metabolites and organelles to eliminate damaged cellular components and/or provide basic metabolic building blocks.
- Urea cycle
A series of chemical reactions involving nitrogen-containing metabolites essential for recycling nitrogen or excreting toxic ammonia waste as urea.
(GSH). Cellular antioxidant composed of glutamate, cysteine and glycine important for quenching damaging reactive oxygen species levels.
The water-soluble dimer of the amino acid cysteine.
- System XC −
Amino acid antiporter system that exchanges glutamate for cystine.
- Oxidative phosphorylation
Oxygen-dependent process by which the proton-motive force between the inner mitochondrial membrane space and matrix is used to generate ATP.
- Hypoxia-inducible factors
(HIFs). Transcription factors, stabilized under conditions of low oxygen levels, targeting the promoters of genes containing hypoxia response elements.
An oxidative, iron-dependent form of programmed cell death.
- Isotope tracing
Application of metabolites in which stable isotopes are incorporated to follow the metabolism or fate of a given nutrient (for example via mass spectroscopy-based metabolomics).
- Acinar–ductal metaplasia
The morphological and transcriptional programmes by which acinar cells dedifferentiate into ductal cells in response to injury or oncogenic stress.
- Pyrimidine synthesis
The metabolic pathway producing the nucleotides uridine, cytidine and thymidine.
- Microsatellite instability
(MSI). An inherent propensity for genomic mutations caused by malfunctioning DNA repair machinery.
Enzymes that catalyse the removal of amido groups.
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Kerk, S.A., Papagiannakopoulos, T., Shah, Y.M. et al. Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment. Nat Rev Cancer 21, 510–525 (2021). https://doi.org/10.1038/s41568-021-00375-9