Tumor Cell Killing Mechanisms of Epidermal Growth Factor Receptor (EGFR) Antibodies Are Not Affected by Lung Cancer-Associated EGFR Kinase Mutations

The epidermal growth factor receptor (EGFR) serves as a molecular target for novel cancer therapeutics such as tyrosine kinase inhibitors (TKI) and EGFR Abs. Recently, specific mutations in the EGFR kinase domain of lung cancers were identified, which altered the signaling capacity of the receptor a...

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Published in:The Journal of immunology (1950) 2008-03, Vol.180 (6), p.4338-4345
Main Authors: Peipp, Matthias, Schneider-Merck, Tanja, Dechant, Michael, Beyer, Thomas, Lammerts van Bueren, Jeroen J, Bleeker, Wim K, Parren, Paul W. H. I, van de Winkel, Jan G. J, Valerius, Thomas
Format: Article
Language:English
Subjects:
Animals
Antibodies, Neoplasm - physiology
Antibodies, Neoplasm - therapeutic use
Antibody-Dependent Cell Cytotoxicity - genetics
Antibody-Dependent Cell Cytotoxicity - immunology
Cell Death - genetics
Cell Death - immunology
Cell Line, Tumor
Epidermal Growth Factor - physiology
ErbB Receptors - genetics
ErbB Receptors - immunology
ErbB Receptors - physiology
Gene Expression Regulation, Enzymologic - immunology
Gene Expression Regulation, Neoplastic - immunology
Growth Inhibitors - physiology
Humans
Lung Neoplasms - enzymology
Lung Neoplasms - immunology
Lung Neoplasms - pathology
Mice
Mutation - immunology
Protein Kinase Inhibitors - therapeutic use
Signal Transduction - genetics
Signal Transduction - immunology
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Summary:The epidermal growth factor receptor (EGFR) serves as a molecular target for novel cancer therapeutics such as tyrosine kinase inhibitors (TKI) and EGFR Abs. Recently, specific mutations in the EGFR kinase domain of lung cancers were identified, which altered the signaling capacity of the receptor and which correlated with clinical response or resistance to TKI therapy. In the present study, we investigated the impact of such EGFR mutations on antitumor cell activity of EGFR Abs. Thus, an EGFR-responsive cell line model was established, in which cells with tumor-derived EGFR mutations (L858R, G719S, delE746-A750) were significantly more sensitive to TKI than wild-type EGFR-expressing cells. A clinically relevant secondary mutation (T790M) abolished TKI sensitivity. Significantly, antitumor effects of EGFR Abs, including signaling and growth inhibition and Ab-dependent cellular cytotoxicity, were not affected by any of these mutations. Somatic tumor-associated EGFR kinase mutations, which modulate growth inhibition by TKI, therefore do not impact the activity of therapeutic Abs in vitro.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.180.6.4338