Targeting cancer cell sialylation with monosaccharide analogues modulates EGFR in colorectal cancer cells

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide, mainly due to resistance to targeted therapies such as Cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR) used in RAS wild-type tumours. Aberrant glycosylation, specifically increased sialylation, has been implicated in tumour progression and therapy resistance. However, its role in the response to EGFR-targeted treatment is not fully understood. This study investigates the impact of inhibition of sialylation on CRC cells' malignant properties and on responsiveness to Cetuximab therapy. Three RAS wild-type CRC cell lines with distinct sialylation profiles, including an ST6GalI overexpressing model, were used as models to evaluate the effects of a pan-sialyltransferase inhibitor. Treatment effectively reduced both terminal α2,3- and α2,6-sialylation at the cell surface and induced a global remodelling of the N-glycome, with decreased sialylated and increased neutral glycans. Functionally, sialylation significantly impaired cell motility without affecting cell viability in any of the cell models. Total EGFR expression and basal activation were not altered, while EGFR glycosylation was directly modulated, particularly terminal α2,6-sialylation. Importantly, EGFR sialylation affected Cetuximab binding and receptor activation in a cell line-dependent manner, with cells bearing α2,6-sialylation showing modified antibody responsiveness. Overall, these findings demonstrate that EGFR sialylation modulates receptor behaviour and Cetuximab response in CRC, highlighting the inhibition of sialylation as a potential strategy to overcome glycosylation-mediated therapeutic resistance.