Evidence of epidermal growth factor receptor expression in uveal melanoma: inhibition of epidermal growth factor-mediated signalling by Gefitinib and Cetuximab triggered antibody-dependent cellular cytotoxicity.

Abstract

Despite advances in surgery and radiotherapy of uveal melanoma (UM), many patients develop distant metastases that poorly respond to therapy. Improved therapies for the metastatic disease are therefore urgently needed. Expression of the epidermal growth factor receptor (EGFR), a target of kinase inhibitors and humanised antibodies in use for several cancers, had been reported. Forty-eight human UMs were analysed by expression profiling. Signalling was tested in three EGFR expressing UM cell lines by Western blotting using phosphorylation specific antibodies for EGFR and the downstream mediators AKT (v-akt murine thymoma viral oncogene homolog) and extracellular signal-regulated kinase (ERK). Evidence for signalling in tumours was obtained through the application of a UM-specific EGF-signature. The EGFR specific kinase inhibitor, Gefitinib and the humanised monoclonal antibody, Cetuximab, were tested for their effect on EGFR signalling. Natural killer cell mediated antibody-dependent cellular cytotoxicity (ADCC) and tumour necrosis factor α (TNF-α) release was analysed for Cetuximab. Fourteen of 48 UMs and three of 14 cell lines (over-)express EGFR, at least in part due to trisomy of the EGFR locus on chromosome 7p12. EGFR and the downstream mediator, AKT, are phosphorylated upon stimulation with EGF in EGFR expressing cell lines. EGFR over-expressing tumours but not EGFR negative tumours show an activated EGF-signature. Gefitinib inhibits EGFR and AKT phosphorylation and Cetuximab induces EGFR phosphorylation but inhibits signalling to AKT induced with EGF. Cetuximab triggers natural killer (NK) cells to lyse EGFR+ cell lines and to release TNF-α. EGFR appears suited as a novel molecular drug target for therapy of uveal melanoma.

• Authors: Adriana Amaro, Valentina Mirisola, Giovanna Angelini, Alessandra Musso, Francesca Tosetti, Alessia I Esposito, Patrizia Perri, Francesco Lanza, Francesca Nasciuti, Carlo Mosci, Roberto Puzone, Sandra Salvi, Mauro Truini, Alessandro Poggi, Ulrich Pfeffer
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 49 Issue 15 Pg. 3353-65 (Oct 2013) ISSN: 1879-0852 [Electronic] England
• PMID: 23849826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• Quinazolines
• ErbB Receptors
• Cetuximab
• Gefitinib

Topics

• Antibodies, Monoclonal, Humanized (pharmacology)
• Antibody-Dependent Cell Cytotoxicity (drug effects)
• Cell Line, Tumor
• Cell Proliferation
• Cetuximab
• ErbB Receptors (antagonists & inhibitors, biosynthesis, metabolism)
• Gefitinib
• Humans
• Melanoma (drug therapy, enzymology, genetics, immunology, metabolism)
• Quinazolines (pharmacology)
• Signal Transduction (drug effects)
• Transcriptome
• Uveal Neoplasms (drug therapy, enzymology, genetics, immunology, metabolism)