title: 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.affiliation: Integrated Molecular Pathology, IRCCS A.O.U. San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Amaro
authors.forename: Valentina
authors.initials: V
authors.lastname: Mirisola
authors.forename: Giovanna
authors.initials: G
authors.lastname: Angelini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musso
authors.forename: Francesca
authors.initials: F
authors.lastname: Tosetti
authors.forename: Alessia I
authors.initials: AI
authors.lastname: Esposito
authors.forename: Patrizia
authors.initials: P
authors.lastname: Perri
authors.forename: Francesco
authors.initials: F
authors.lastname: Lanza
authors.forename: Francesca
authors.initials: F
authors.lastname: Nasciuti
authors.forename: Carlo
authors.initials: C
authors.lastname: Mosci
authors.forename: Roberto
authors.initials: R
authors.lastname: Puzone
authors.forename: Sandra
authors.initials: S
authors.lastname: Salvi
authors.forename: Mauro
authors.initials: M
authors.lastname: Truini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pfeffer
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000098943:Uveal Melanoma
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D011799:Quinazolines; D066246:ErbB Receptors; D000068818:Cetuximab; D000077156:Gefitinib
keywords: Antibody-dependent cellular cytotoxicity; Epidermal growth factor receptor; Targeted therapy; Tyrosine kinase