Abstract
The anti-ErbB2 antibody trastuzumab has currently been approved for ErbB2-positive gastric cancer. Despite the effectiveness of trastuzumab, resistance is common. Thus, there is an urgent need to overcome trastuzumab resistance. Here, we obtain a trastuzumab-resistant cell line, which is derived from the human gastric cancer NCI-N87 cell line, by modeling the development of acquired resistance in patients. Our data show that combining trastuzumab and cetuximab leads to a significant decrease in EGFR/ErbB2 heterodimers and signaling compared with either antibody alone, and the combination results in greater antitumor activity against the trastuzumab-resistant NCI-N87 cell line, both in vitro and in vivo, suggesting that a combined EGFR/ErbB2 inhibition may overcome trastuzumab resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal, Humanized / administration & dosage
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects
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Blotting, Western
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Cell Proliferation / drug effects
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Cetuximab
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Drug Resistance, Neoplasm / drug effects*
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Female
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Humans
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Immunoprecipitation
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Mice
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Mice, Inbred BALB C
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Protein Multimerization / drug effects*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Receptor, ErbB-2 / antagonists & inhibitors*
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects*
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Stomach Neoplasms / drug therapy*
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Stomach Neoplasms / metabolism
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Stomach Neoplasms / pathology
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Trastuzumab
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Tumor Cells, Cultured
Substances
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Antibodies, Monoclonal, Humanized
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RNA, Messenger
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EGFR protein, human
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ERBB2 protein, human
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ErbB Receptors
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Receptor, ErbB-2
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Trastuzumab
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Cetuximab