Abstract
To understand the role of human epidermal growth factor receptor (hEGFR) kinase domain mutations in lung tumorigenesis and response to EGFR-targeted therapies, we generated bitransgenic mice with inducible expression in type II pneumocytes of two common hEGFR mutants seen in human lung cancer. Both bitransgenic lines developed lung adenocarcinoma after sustained hEGFR mutant expression, confirming their oncogenic potential. Maintenance of these lung tumors was dependent on continued expression of the EGFR mutants. Treatment with small molecule inhibitors (erlotinib or HKI-272) as well as prolonged treatment with a humanized anti-hEGFR antibody (cetuximab) led to dramatic tumor regression. These data suggest that persistent EGFR signaling is required for tumor maintenance in human lung adenocarcinomas expressing EGFR mutants.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / genetics*
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Adenocarcinoma / pathology
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Adenocarcinoma, Bronchiolo-Alveolar / drug therapy
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Adenocarcinoma, Bronchiolo-Alveolar / genetics
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Adenocarcinoma, Bronchiolo-Alveolar / pathology
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Animals
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Antibodies, Monoclonal / therapeutic use
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / therapeutic use*
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Cetuximab
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Enzyme Activation
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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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Erlotinib Hydrochloride
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Exons
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Humans
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Lung / metabolism
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics*
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Lung Neoplasms / pathology
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Mice
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Mice, Transgenic
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Mutation
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Protein Structure, Tertiary
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Quinazolines / therapeutic use
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Quinolines / therapeutic use
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Quinazolines
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Quinolines
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Erlotinib Hydrochloride
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ErbB Receptors
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neratinib
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Cetuximab