Overexpression of the epidermal growth factor (EGF) receptor, a hallmark of aerodigestive squamous cell carcinoma of the head and neck (SCCHN), correlates with aggressive tumor behavior. There is evidence that SCCHN cells auto-activate their EGF receptors. The receptor has therefore attracted interest as a potential therapeutic target. We tested the in vitro therapeutic efficacy of PD153035-a potent, specific inhibitor of the tyrosine kinase intrinsic to the EGF receptor-by employing a well-characterized cell line derived from human gingival SCCHN. DNA-synthesis and cell number were assayed for growth-inhibitory effects, phosphorylation of the EGF receptor was quantitated by immunoblot, and cell apoptosis was detected by terminal deoxytransferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling (TUNEL) in situ assay. PD 153035, at nanomolar concentrations, inhibited autophosphorylation of the EGF receptor induced by EGF stimulation and the inhibition occurred in a dose-dependent manner. Under the same conditions, PD 153035 inhibited cell growth, and induced apoptosis of SCCHN cells in vitro. We conclude that selective inhibition of the EGF receptor tyrosine kinase completely abolishes EGF receptor phosphorylation resulting from receptor stimulation, and results in growth inhibition and apoptosis of SCCHN cells in vitro. By inducing cytostasis and apoptosis, this new class of inhibitors may be of therapeutic value against SCCHN.
Bibliographical noteFunding Information:
Supported in part by the American Society for Head and Neck Surgery, the Medical Research Fund of the United States Department of Veterans Affairs, and NCI Research Grant, CA-15062. We gratefully acknowledge Dr T. Kuroki, Department of Cancer Cell Research, University of Tokyo, for providing human cell lines developed from squamous cell carcinomas of the head and neck. The authors are grateful to Dr David Fry, Division of Cancer Research, Parke-Davis, for generously providing the EGF-receptor tyrosine kinase inhibitor (PD153035), and for his critical reading and discussions of the manuscript.
- Cancer treatment
- Cell signalling
- Growth factor