Abstract
Extracellular S468R mutation of the epidermal growth factor receptor (EGFR) was recently identified as the cause of resistance to cetuximab, a widely used drug in colorectal cancer treatment. Here, we have determined the binding free energies of cetuximab's Fab V(H)-V(L) domains and endogenous EGF ligand to wild type and S468R EGFR by high-throughput molecular dynamics. This work provides a possible mechanism of resistance in terms of increased competition, an hypothesis that can be further validated experimentally.
Publication types
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Letter
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Monoclonal, Humanized / chemistry*
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Antineoplastic Agents / chemistry*
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Cetuximab
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Colorectal Neoplasms / drug therapy
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Drug Resistance, Neoplasm / genetics
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Epidermal Growth Factor / chemistry
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / chemistry*
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ErbB Receptors / genetics
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Humans
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Ligands
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Molecular Dynamics Simulation*
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Mutation
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Neuregulin-1 / chemistry
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Single-Domain Antibodies / chemistry*
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Thermodynamics
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Transforming Growth Factor alpha / chemistry
Substances
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Ligands
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Neuregulin-1
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Single-Domain Antibodies
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Transforming Growth Factor alpha
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heregulin alpha
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Epidermal Growth Factor
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EGFR protein, human
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ErbB Receptors
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Cetuximab