Sequenzanalyse des Epidermal Growth Factor Receptors bei Plattenepithel-Karzinom-Zelllinien des Kopf-Hals-Bereiches und ihre potentielle Bedeutung für die Pathogenese

Plattenepithelkarzinome stellen mehr als 90% aller Malignome des oberen Aerodigestivtraktes dar. Diese auch als HNSCC (Head and Neck Squamous Cell Carcinomas) bezeichneten Tumoren überexprimieren in bis zu 100% den Epidermalen Wachstumsfaktor Rezeptor (EGFR; Epidermal Growth Factor Receptor), wobei...

Full description

Saved in:
Bibliographic Details
Main Author: Krohn, Vanessa
Contributors: Mandic, R. (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2011
Online Access:PDF Full Text
Tags: Add Tag
No Tags, Be the first to tag this record!

The epidermal growth factor receptor (EGFR, ErbB-1, HER-1) is overexpressed in many epithelial tumors, particularly head and neck squamous cell carcinomas (HNSCCs) and is related to poor prognosis. For non-small cell lung cancer (NSCLC) it was found that activating mutations in the kinase domain of the receptor predicted a high response-rate to EGFR-specific kinase inhibitors. The goal of the present study was to investigate potential sequence changes of EGFR in HNSCC cells and to determine their possible role in tumor biology. The whole EGFR coding sequence of eleven previously well-characterized HNSCC cell lines was determined by RT-PCR sequencing. The response of the cells to the kinase inhibitor AG1478 and the monoclonal anti-EGFR antibody cetuximab was evaluated by cell cycle and Western blot analysis. None of the cell lines exhibited EGFR mutations. However, 4 out of the 11 (36%) cell lines harboured the K497 polymorphism in the receptor. The K497 cells appeared on average to be more sensitive to inhibitor treatment. This effect was particularly pronounced in the AG1478-treated tumor cells and was associated with the level of extracellular-signal regulated kinase-1/2 phosphorylation which appeared more efficiently inhibited in the cell lines exhibiting the K497 EGFR polymorphism. EGFR mutations are a rare event in HNSCC cell lines and, consistent with previous studies the EGFR codon 497 polymorphism could play a significant role in HNSCC disease and therapy response.