title: 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-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.
authors.affiliation: 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.
authors.forename: Mohit P
authors.initials: MP
authors.lastname: Mathew
authors.affiliation: 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.
authors.forename: Elaine
authors.initials: E
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Saeui
authors.affiliation: 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.
authors.forename: Patawut
authors.initials: P
authors.lastname: Bovonratwet
authors.affiliation: 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.
authors.forename: Lingshu
authors.initials: L
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhattacharya
authors.affiliation: 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.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Yarema
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000737:chemistry* / Q000494:pharmacology; D000077156:Gefitinib; D006031:Glycosylation; D006801:Humans; D060847:Metabolic Engineering; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D050791:STAT Transcription Factors; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Drug synergy; Epidermal growth factor receptor; Metabolic oligosaccharide engineering; Pancreatic cancer; Receptor tyrosine kinase inhibitor; Sialylation