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

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 ₃ManNAc, a “metabolic glycoengineering” drug candidate that increased sialylation by ∼12-fold. Consistent with genetic methods previously used to increase EGFR sialylation, this small molecule reduced EGF binding, EGFR transphosporylation, 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, l,3,4- O-Bu ₃ManNAz, which is the azido-modified counterpart to l,3,4- O-Bu ₃ManNAc, provided a similar benefit thereby establishing a broad-based foundation to extend a “metabolic glycoengineering” approach to clinical applications.

Graphical abstract