TY - JOUR
T1 - Metabolic glycoengineering sensitizes drug-resistant pancreatic cancer cells to tyrosine kinase inhibitors erlotinib and gefitinib
AU - Mathew, Mohit P.
AU - Tan, Elaine
AU - Saeui, Christopher T.
AU - Bovonratwet, Patawut
AU - Liu, Lingshu
AU - Bhattacharya, Rahul
AU - Yarema, Kevin J.
N1 - Funding Information:
Funding was obtained from the National Institutes of Health , NCI grant R01CA112314 .
Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.
PY - 2015/3/15
Y1 - 2015/3/15
N2 - 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.
AB - 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.
KW - Drug synergy
KW - Epidermal growth factor receptor
KW - Metabolic oligosaccharide engineering
KW - Pancreatic cancer
KW - Receptor tyrosine kinase inhibitor
KW - Sialylation
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U2 - 10.1016/j.bmcl.2015.01.060
DO - 10.1016/j.bmcl.2015.01.060
M3 - Article
C2 - 25690786
AN - SCOPUS:84923920602
SN - 0960-894X
VL - 25
SP - 1223
EP - 1227
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 6
ER -