Metabolic glycoengineering sensitizes drug-resistant pancreatic cancer cells to tyrosine kinase inhibitors erlotinib and gefitinib

Mohit P Mathew; Elaine Tan; Christopher T Saeui; Patawut Bovonratwet; Lingshu Liu; Rahul Bhattacharya; Kevin J Yarema

doi:10.1016/j.bmcl.2015.01.060

Metabolic glycoengineering sensitizes drug-resistant pancreatic cancer cells to tyrosine kinase inhibitors erlotinib and gefitinib

Bioorg Med Chem Lett. 2015 Mar 15;25(6):1223-7. doi: 10.1016/j.bmcl.2015.01.060. Epub 2015 Feb 4.

Authors

Mohit P Mathew¹, Elaine Tan¹, Christopher T Saeui¹, Patawut Bovonratwet¹, Lingshu Liu¹, Rahul Bhattacharya¹, Kevin J Yarema²

Affiliations

¹ Department of Biomedical Engineering and the Translational Tissue Engineering Center, The Johns Hopkins University, 5029 Robert H. & Clarice Smith Building, 400 North Broadway, Baltimore, MD 21231, USA.
² Department of Biomedical Engineering and the Translational Tissue Engineering Center, The Johns Hopkins University, 5029 Robert H. & Clarice Smith Building, 400 North Broadway, Baltimore, MD 21231, USA. Electronic address: kyarema1@jhu.edu.

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-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.

Keywords: Drug synergy; Epidermal growth factor receptor; Metabolic oligosaccharide engineering; Pancreatic cancer; Receptor tyrosine kinase inhibitor; Sialylation.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm / drug effects
Drug Synergism
ErbB Receptors / chemistry
ErbB Receptors / metabolism
Erlotinib Hydrochloride / chemistry*
Erlotinib Hydrochloride / pharmacology
Gefitinib
Glycosylation
Humans
Metabolic Engineering*
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Phosphorylation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Quinazolines / chemistry*
Quinazolines / pharmacology
STAT Transcription Factors / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Quinazolines
STAT Transcription Factors
Erlotinib Hydrochloride
ErbB Receptors
Gefitinib

Abstract

Publication types

MeSH terms

Substances

Grants and funding