Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy

Increasing knowledge of the structure and function of the epidermal growth factor receptor (EGFR) subfamily of tyrosine kinases and of their role in t he initiation and progression of various cancers has, in recent years, prov ided the impetus for a substantial research effort aimed at developing new anticancer therapies that target specific components of the EGFR signal tra nsduction pathway. Selective compounds have been developed that target eith er the extracellular ligand-binding region of the EGFR or the intracellular tyrosine kinase region, resulting in interference with the signalling path ways that modulate mitogenic and other cancer-promoting responses (e.g. cel l motility, cell adhesion, invasion and angiogenesis). Potential new antica ncer agents that target the extracellular ligand-binding region of the rece ptor include a number of monoclonal antibodies, immunotoxins and ligand-bin ding cytotoxic agents. Agents that target the intracellular tyrosine kinase region include small molecule tyrosine kinase inhibitors (TKIs), which act by interfering with ATP binding to the receptor, and various other compoun ds that act at substrate-binding regions or downstream components of the si gnalling pathway. Currently, the most advanced of the newer therapies undergoing clinical dev elopment are antireceptor monoclonal antibodies (e.g. trastuzumab and cetux imab) and a number of small molecule EGFR-TKIs principally of the quinazoli ne and pyrazolo-pyrrolo-pyridopyrimidine inhibitor structural classes. The latter group of compounds offers several advantages in cancer chemotherapy, including the possibility of inhibiting specific deregulated pathways in c ancer cells while having minimal effects on normal cell function. They also have favourable pharmacokinetic and pharmacodynamic properties and low tox icity, and some TKIs such as the reversible inhibitor ZD1839 ('Iressa')(1,2 ) are now undergoing phase LI to III clinical trials. In addition, the accu mulation of evidence from laboratory studies strongly suggests that EGFR-se lective TKIs will have synergistic effects with other antitumour agents or therapy such as cytostatic agents, conventional cytotoxic drugs and radioth erapy. As our knowledge of signal transduction pathways in cancer increases , it is hoped that further advances in this area will allow the therapeutic potential of these compounds as anticancer agents to be realised.