Epidermal growth factor receptor signaling and glutamine metabolism (EGFR-Glutamine Axis)

The interaction between Epidermal Growth Factor Receptor (EGFR) signaling and glutamine metabolism represents a critical metabolic reprogramming event in oncogenesis. EGFR activation triggers downstream cascades, including the PI3K/Akt/mTOR and MAPK pathways, which collectively enhance the expression of glutamine transporters and the enzyme glutaminase (GLS) (PMID: 23911320). This shift ensures a steady supply of glutamine-derived intermediates for the TCA cycle, nucleotide biosynthesis, and antioxidant defense via glutathione production (PMID: 28611082). In clinical contexts, such as EGFR-mutant non-small cell lung cancer, tumors often become addicted to glutamine, making this axis a significant therapeutic vulnerability. Consequently, dual inhibition of EGFR and glutamine metabolism is being explored to circumvent resistance to standard EGFR tyrosine kinase inhibitors (PMID: 30217985). This synergy highlights the importance of targeting both signaling and metabolic nodes to improve patient outcomes in refractory cancers.

Other names

EGFR-mediated metabolic reprogrammingEGFR-glutamine metabolic couplingEGFR-GLS axisEGFR-driven glutaminolysis

The mechanism involves the simultaneous or sequential inhibition of the EGFR tyrosine kinase domain to block oncogenic proliferative signaling and the inhibition of glutaminase (GLS) to disrupt the supply of carbon and nitrogen required for tumor cell survival and antioxidant capacity.