Epidermal growth factor receptor bearing cancer-associated β1-6 branched complex N-glycans (EGFR-β1,6-GlcNAc)

The Epidermal Growth Factor Receptor (EGFR) bearing cancer-associated β1-6 branched complex N-glycans is a specific glycoform of the EGFR protein characterized by aberrant post-translational modifications. This modification is primarily catalyzed by the enzyme N-acetylglucosaminyltransferase V (MGAT5 or GnT-V), which adds β1-6 GlcNAc branches to the N-glycan core (Lau et al., 2007, Science, PMID: 17412921). In the context of cancer, these branched glycans facilitate the formation of a galectin-3-mediated molecular lattice on the cell surface, which inhibits EGFR internalization and degradation, thereby leading to constitutive or hypersensitive signaling (Partridge et al., 2004, J Biol Chem, PMID: 15150444). This aberrant glycosylation promotes tumor progression, epithelial-mesenchymal transition (EMT), and metastasis (Guo et al., 2014, FEBS J, PMID: 25646743). While traditional EGFR inhibitors like cetuximab and gefitinib target the protein or kinase domain, emerging therapeutic strategies aim to specifically target this glycoform to improve selectivity and overcome resistance (An et al., 2023, Cancers, PMID: 36831476). Targeting the β1-6 branched N-glycans offers a potential avenue for precision oncology by distinguishing between the EGFR found on healthy versus cancerous tissues.

Other names

GnT-V modified EGFRMGAT5-modified EGFRβ1,6-GlcNAc-branched EGFRGlycosylated EGFRCancer-associated EGFR glycoform

Drugs targeting this molecule primarily act by blocking the extracellular ligand-binding domain, inhibiting the intracellular tyrosine kinase activity, or specifically recognizing the aberrant glycan structure to induce antibody-dependent cellular cytotoxicity (ADCC) and disrupt the galectin-mediated lattice that stabilizes the receptor on the cell surface (Lau et al., 2007, Science, PMID: 17412921; Guo et al., 2014, FEBS J, PMID: 25646743).