Treatment of HNSCC cell lines with the EGFR-specific inhibitor cetuximab (Erbitux) results in paradox phosphorylation of tyrosine 1173 in the receptor

Robert Mandic; Chantal J Rodgarkia-Dara; Li Zhu; Benedikt J Folz; Michael Bette; Eberhard Weihe; Andreas Neubauer; Jochen A Werner

doi:10.1016/j.febslet.2006.07.064

Treatment of HNSCC cell lines with the EGFR-specific inhibitor cetuximab (Erbitux) results in paradox phosphorylation of tyrosine 1173 in the receptor

FEBS Lett. 2006 Sep 4;580(20):4793-800. doi: 10.1016/j.febslet.2006.07.064. Epub 2006 Aug 4.

Authors

Robert Mandic¹, Chantal J Rodgarkia-Dara, Li Zhu, Benedikt J Folz, Michael Bette, Eberhard Weihe, Andreas Neubauer, Jochen A Werner

Affiliation

¹ Department of Otolaryngology, Head and Neck Surgery, Philipps University Marburg, Deutschhausstrasse 3, D-35037 Marburg, Germany. [email protected]

PMID: 16904111
DOI: 10.1016/j.febslet.2006.07.064

Abstract

Overexpression of the epidermal growth factor receptor (EGFR, ErbB1, HER1) is frequent in head and neck squamous cell carcinomas (HNSCCs) and correlates with disease progression. Inhibition of EGFR with the kinase inhibitor AG1478 abolished receptor phosphorylation and reduced cell proliferation. However, treatment of HNSCC cells with cetuximab (Erbitux), a monoclonal antibody designed to block the EGFR ligand binding site, led to paradox EGFR activation due to hyperphosphorylation of tyrosine 1173, however, with a concomitant reduction in Erk1/2 phosphorylation levels. No pronounced influence on cell proliferation levels could be observed after treatment with this antibody. Since cetuximab appears able to activate EGFR in HNSCC cell lines, it is necessary to rethink the exact mechanisms by which cetuximab that recently was approved for the treatment of advanced head and neck cancer, inhibits tumor growth.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Monoclonal / therapeutic use*
Antibodies, Monoclonal, Humanized
Antineoplastic Agents / metabolism
Antineoplastic Agents / therapeutic use*
Carcinoma, Squamous Cell* / drug therapy
Carcinoma, Squamous Cell* / pathology
Cell Cycle / physiology
Cell Line, Tumor
Cell Survival
Cetuximab
Cisplatin / metabolism
Enzyme Inhibitors / metabolism
Epidermal Growth Factor / metabolism
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / genetics
ErbB Receptors / metabolism*
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
Extracellular Signal-Regulated MAP Kinases / metabolism
Head and Neck Neoplasms* / drug therapy
Head and Neck Neoplasms* / pathology
Humans
Phosphorylation
Quinazolines
Tyrosine / metabolism*
Tyrphostins / metabolism

Substances

Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Antineoplastic Agents
Enzyme Inhibitors
Quinazolines
Tyrphostins
RTKI cpd
Tyrosine
Epidermal Growth Factor
ErbB Receptors
Extracellular Signal-Regulated MAP Kinases
Cetuximab
Cisplatin