INHIBITION OF EPIDERMAL GROWTH-FACTOR RECEPTOR GENE-EXPRESSION AND FUNCTION DECREASES PROLIFERATION OF HEAD AND NECK SQUAMOUS CARCINOMA BUTNOT NORMAL MUCOSAL EPITHELIAL-CELLS

Previous reports have shown that fresh tissues and cell lines from pat ients with squamous cell carcinoma of the head and neck (SCCHN) overex press transforming growth factor alpha (TGF-alpha) and its receptor, t he epidermal growth factor receptor (EGFR) at both the mRNA and protei n levels. Protein localization studies confirm that TGF-alpha and EGFR are produced by the same epithelial cells in tissues from head and ne ck cancer patients further supporting an autocrine growth pathway. Usi ng three strategies, we examined the hypothesis that downmodulation of EGFR would reduce the proliferation of SCCHN cells. We targeted EGFR mRNA using antisense oligonucleotides and the mature EGFR protein at t wo sites, the ligand-binding domain and the kinase domain, and determi ned the effects of this targeting on SCCHN proliferation. Treatment of several SCCHN cell lines with a pair of antisense oligodeoxynucleotid es directed against the translation start site and first intron-exon s plice junction of the human EGFR gene resulted in decreased EGFR prote in production and inhibited growth by 86% compared to a 13% reduction in cells treated with sense oligonucleotides (P=0.03). Growth inhibiti on was specific for carcinoma cells since the same EGFR antisense olig onucleotides had no effect on the proliferation of normal mucosa cells harvested from non-cancer patients. Two monoclonal antibodies which b lock ligand binding to EGFR (MAbs 425 and 528) inhibited the growth of several SCCHN cell lines by up to 97% which suggests that EGFR is par ticipating in an autocrine pathway in SCCHN that is, at least in part, external. An EGFR-specific tyrosine kinase inhibitor (PD 153035) was found to inhibit EGFR phosphorylation in SCCHN cell lines and to reduc e growth by 68% although it had no effect on the growth rate of normal mucosal epithelial cells. These experiments indicate that EGFR gene e xpression and function is critical for SCCHN cell growth but not for g rowth of normal mucosa cells and therefore may serve as a tumor-specif ic target for preventive and therapeutic strategies in head and neck c ancer.