title: Tumor cell killing mechanisms of epidermal growth factor receptor (EGFR) antibodies are not affected by lung cancer-associated EGFR kinase mutations.
abstract: 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.
authors.affiliation: Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Peipp
authors.forename: Tanja
authors.initials: T
authors.lastname: Schneider-Merck
authors.forename: Michael
authors.initials: M
authors.lastname: Dechant
authors.forename: Thomas
authors.initials: T
authors.lastname: Beyer
authors.forename: Jeroen J
authors.initials: JJ
authors.lastname: Lammerts van Bueren
authors.forename: Wim K
authors.initials: WK
authors.lastname: Bleeker
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
authors.forename: Jan G J
authors.initials: JG
authors.lastname: van de Winkel
authors.forename: Thomas
authors.initials: T
authors.lastname: Valerius
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000502:physiology* / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics / Q000276:immunology*; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D000912:Antibodies, Neoplasm; D006131:Growth Inhibitors; D047428:Protein Kinase Inhibitors; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors