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* Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany;
Genmab, Utrecht, The Netherlands; and
Department of Immunology, Immunotherapy Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 M.P. and T.S.-M. contributed equally to this work.
2 Current address: Section of Stem Cell Transplantation and Immunotherapy, Christian-Albrechts-University, Kiel, Germany.
3 Address correspondence and reprint requests to Dr. Thomas Valerius, Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Schittenhelmstrasse 12, 24105 Kiel, Germany. E-mail address: valerius{at}nephro.uni-kiel.de
4 Abbreviations used in this paper: EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; wt, wild type; NCSLC, non-small cell lung cancer; EGF, epidermal growth factor; ADCC, Ab-dependent cellular cytotoxicity; m, murine; MNC, mononuclear effector cell.
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