Abstract A101: Dose-related suppression of rat oral carcinogenesis by the EGF receptor-tyrosine kinase inhibitor, gefitinib

Abstract

Abstract Activation of the epidermal growth factor receptor (EGFR) stimulates signal transduction pathways that regulate cell proliferation and may be causally involved in carcinogenesis. Recent data suggest that EGFR expression is a predictive biomarker for the risk of oral cancer in humans, and that alterations in EGFR expression or action may be directly involved in oral carcinogenesis. Gefitinib (N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)-quinazolin-4-amine; ZD1839; Iressa) is a specific inhibitor of EGFR tyrosine kinase (EGFR-TK). The present study was performed to evaluate the activity of gefitinib as an inhibitor of oral cancer induction in rats. Squamous cell carcinomas of the tongue were induced in male F344 rats by drinking water administration of 4-nitroquinoline-1-oxide (NQO; 20 ppm for 10 weeks). After NQO administration was completed, rats were randomized into groups of 25 and received [a] unsupplemented basal diet only (dietary control); [b] basal diet + gefinitib (50 mg/kg diet); or [c] basal diet + gefinitib (100 mg/kg diet). All diets were fed continuously from week 10 until the end of the study at week 26. Dietary administration of gefinitib induced a dose-related inhibition of oral cancer induction (cancer incidences of 57% and 36% in low and high dose groups, respectively, versus 80% incidence in the dietary control group; p < 0.01), and prevented the body weight loss that is commonly seen in this model in animals with advanced oral cancer. While reducing the incidence of invasive oral cancers, gefinitib increased the incidence of squamous epithelial hyperplasia (35% and 40% in low and high dose groups, respectively, versus 16% in dietary controls); the increased incidence of oral epithelial hyperplasia suggests that gefinitib prevented the progression of hyperplastic lesions into invasive oral cancers. Gefinitib induced no evidence of systemic toxicity in any treated animal. PCR analysis demonstrated comparable levels of EGFR transcripts in oral cancers and site-matched phenotypically normal oral tissues harvested from age-matched animals treated with NQO. Thus, the utility of EGFR-TK as a target for oral cancer chemoprevention in this model is not clearly associated with differential expression of EGFR in neoplastic oral tissues. These data demonstrate that EGFR inhibitors may be useful for the prevention of oral cancer, and that overexpression of EGFR in these cancers is not essential for chemopreventive efficacy. (Supported by N01-CN-85163 and N01-CN-25113 from the NCI.) Citation Information: Cancer Prev Res 2010;3(12 Suppl):A101.