Metabolic glycoengineering sensitizes drug-resistant pancreatic cancer cells to tyrosine kinase inhibitors erlotinib and gefitinib
2015
Abstract 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 -Bu 3 ManNAc, 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 -Bu 3 ManNAz, which is the azido-modified counterpart to 1,3,4- O -Bu 3 ManNAc, provided a similar benefit thereby establishing a broad-based foundation to extend a ‘metabolic glycoengineering’ approach to clinical applications.
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