Metabolic Glycoengineering Sensitizes Drug-Resistant Pancreatic Cancer Cells to Tyrosine Kinase Inhibitors Erlotinib and Gefitinib

Metastatic human pancreatic cancer cells (the SW1990 line) that are resistant to the EGFR-targeting tyrosine kinase inhibitor drugs (TKI) erlotinib and gefitinib were treated with 1,3,4-O-Bu3ManNAc, a 'metabolic glycoengineering' drug candidate that increased sialylation by ∼2-fold. Consistent with genetic methods previously used to increase EGFR sialylation, this small molecule reduced EGF binding, EGFR transphosphorylation, and downstream STAT activation. Significantly, co-treatment with both the sugar pharmacophore and the existing TKI drugs resulted in strong synergy, in essence re-sensitizing the SW1990 cells to these drugs. Finally, 1,3,4-O-Bu3ManNAz, which is the azido-modified counterpart to 1,3,4-O-Bu3ManNAc, provided a similar benefit thereby establishing a broad-based foundation to extend a 'metabolic glycoengineering' approach to clinical applications.