Abstract
EGF receptor (EGFR)-mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKI). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models and human patients. Because afatinib is also a potent HER2 inhibitor, we investigated the role of HER2 in EGFR-mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. FISH analysis revealed that HER2 was amplified in 12% of tumors with acquired resistance versus only 1% of untreated lung adenocarcinomas. Notably, HER2 amplification and EGFR(T790M) were mutually exclusive. Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR-TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR-mutant tumors with acquired resistance to EGFR-TKIs.
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 / metabolism
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Adenocarcinoma of Lung
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Afatinib
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Animals
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal / therapeutic use
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Cell Line, Tumor
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Cetuximab
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Class I Phosphatidylinositol 3-Kinases
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Drug Resistance, Neoplasm / genetics*
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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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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / genetics*
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Lung Neoplasms / metabolism
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Mice
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Mice, Nude
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Molecular Targeted Therapy
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Mutation
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Phosphatidylinositol 3-Kinases / genetics
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Quinazolines / pharmacology
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Quinazolines / therapeutic use
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RNA Interference
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RNA, Small Interfering
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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*
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Quinazolines
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RNA, Small Interfering
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Afatinib
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Erlotinib Hydrochloride
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Phosphatidylinositol 3-Kinases
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Class I Phosphatidylinositol 3-Kinases
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PIK3CA protein, human
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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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Cetuximab