Metabolic Adaptations in KRAS-Driven Cancers

Oncogenic mutations in KRAS drive extensive remodelling of cellular metabolism to support tumour initiation, maintenance and progression. Central to this rewiring is enhanced uptake and utilisation of glucose and glutamine, which fuel glycolysis, the tricarboxylic acid cycle and biosynthetic pathways. KRAS-mutant cells often increase macropinocytosis and autophagy to scavenge extracellular proteins and lipids, supplying amino acids and fatty acids for anabolic growth. Altered lipid handling, including elevated fatty acid oxidation or storage, maintains energy homeostasis and redox balance. Furthermore, nutrient stress and hypoxia prompt adaptive responses through the hexosamine biosynthesis pathway and oxidative stress regulators, enabling cancer cells to survive in adverse microenvironments. These metabolic dependencies create vulnerabilities that can be exploited therapeutically, from inhibition of key transporters to targeting stress-response enzymes. Collectively, understanding the spectrum of KRAS-driven metabolic adaptations offers routes to disrupt tumour bioenergetics and biosynthesis while sparing normal tissues.

Research from Nature Portfolio

Recent studies have revealed a critical role for the mitochondrial carrier SLC25A22 in KRAS-mutant colorectal cancer. In vivo models demonstrated that SLC25A22 promotes asparagine synthesis, driving SRC phosphorylation and downstream ERK-ETS2 signalling. This axis stimulates secretion of chemokines that recruit suppressive myeloid cells, thereby linking metabolic flux to immune evasion. Genetic or pharmacological inhibition of SLC25A22 impaired tumour growth and synergised with anti-PD1 therapy to restore CD8+ T-cell activity.

Foundational work in pancreatic ductal adenocarcinoma uncovered how KRAS activation sustains nucleotide pools through a MAPK-MYC-regulated non-oxidative pentose phosphate pathway. Oncogenic KRAS upregulates RPIA, enhancing ribose production and nucleotide synthesis to support rapid proliferation. Inhibition of the pentose phosphate pathway or pyrimidine biosynthesis preferentially suppressed growth of KRAS-dependent cells and sensitised resistant models to MEK inhibitors, pointing to nucleotide metabolism as a therapeutic target.

Metabolic Adaptations in KRAS-Driven Cancers publication trend

The graph below shows the total number of articles in metabolic adaptations in kras-driven cancers across all publications each year (not limited to Nature Index journals).

Technical terms

Anaplerosis: The process by which intermediates of the tricarboxylic acid cycle are replenished, typically via amino acid or glutamine metabolism, to sustain energy production and biosynthesis.

Macropinocytosis: A form of endocytosis in which cells engulf large volumes of extracellular fluid, enabling uptake of proteins and nutrients for lysosomal degradation and metabolic utilisation.

Hexosamine biosynthesis pathway: A metabolic route that converts glucose and glutamine into UDP-N-acetylglucosamine, supporting protein glycosylation and regulating stress responses under nutrient limitation.

Methuosis: A non-apoptotic cell death characterised by excessive accumulation of vacuoles derived from macropinosomes, leading to rupture of the plasma membrane and cell lysis.

References

1. Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer. Nature Communications (2023).
2. Nutlin-3a induces KRAS mutant/p53 wild type lung cancer specific methuosis-like cell death that is dependent on GFPT2. Journal of Experimental & Clinical Cancer Research (2023).
3. SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis. JCI Insight (2023).
4. Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nature Communications (2018).
5. KRAS-Driven Metabolic Rewiring Reveals Novel Actionable Targets in Cancer. Frontiers in Oncology (2019).