Epidermal growth factor receptor tyrosine kinase inhibitors as potential cancer chemopreventives

Among the most important targets for chemopreventive intervention and drug development are deregulated signal transduction pathways, and protein tyrosine kinases are key components of these pathways. Loss of tyrosine kinase regulatory mechanisms has been implicated in neoplastic growth; indeed, many oncogenes code for either receptor or cellular tyrosine kinases. Because of its deregulation in many cancers (bladder, breast, cervix, colon, esophagus, head and neck, lung, and prostate), the epidermal growth factor receptor (EGFR) has been selected as a potential target for chemoprevention. Because growth factor networks are redundant, selective inhibition of signaling pathways activated in precancerous and cancerous cells should be possible. Requirements for specific EGFR inhibitors include specificity for EGFR, high potency, activity in intact cells, and activity in vivo. Inhibition of autophosphorylation is preferred, because it should result in total blockade of the signaling pathway. Inhibitors that compete with substrate rather than at the ATP-binding site are also preferable, because they are not as likely to inhibit other ATP-using cellular enzymes. Several classes of specific EGFR inhibitors have been synthesized recently, including structures such as benzylidene malononitriles, dianilinophthalimides, quinazolines, pyrimidines, [(alkylamino)methyl]-acrylophenones, enollactones, dihydroxybenzylaminosalicylates, 2-thioindoles, aminoflavones, and tyrosine analogue-containing peptides. A possible testing strategy for the development of these and other EGFR inhibitors as chemopreventive agents includes the following steps: (a) determine EGFR tyrosine kinase inhibitory activity in vitro; (b) evaluate EGFR specificity and selectivity (relative to other tyrosine kinases and other protein kinases); (c) determine inhibition of EGFR-mediated effects in intact cells; (d) determine inhibition of EGFR-mediated effects in vivo (e.g., in nude mouse tumor xenografts); and (e) determine chemopreventive efficacy in vivo (e.g., in the hamster buccal pouch or mouse or rat bladder).