Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily - Role as anticancer agents

Abnormal cell signal transduction arising from protein tyrosine kinases has been implicated in the initiation and progression of a variety of human ca ncers. Over the past 2 decades pharmaceutical and university laboratories h ave been involved in a tremendous effort to develop compounds that can sele ctively modulate these abnormal signalling pathways. Targeting receptor tyr osine kinases, especially the epidermal growth factor receptor subfamily, h as been at the forefront of this effort as a result of strong clinical data correlating over-expression of these receptors with more aggressive cancer s. There are a variety of strategies under development for inhibiting the kina se activity of these receptors, targeting both the extracellular and intrac ellular domains. Antibody-based approaches, immunotoxins and ligand-binding cytotoxic agents use the extracellular domain for targeted tumour therapy. Small molecule inhibitors target the intracellular catalytic region by int erfering with ATP binding, while nonphosphorylatable peptides are aimed at the intracellular substrate binding region, Compounds that inhibit subseque nt downstream signals from the receptor by interrupting intracellular prote in recognition sequences are also being investigated. In the past 5 years enormous progress has been made in developing tyrosine kinase inhibitor compounds with sufficient potency, bioavailability and sel ectivity against this subfamily of receptor tyrosine kinases. The anti-HER2 monoclonal antibody, trastuzumab, for patients with metastatic breast canc er is the first of these inhibitor compounds to gain FDA approval. However, preclinical and clinical trials are ongoing with a variety of other monocl onal antibodies, immunotoxins, and small molecule quinazoline and pyrimidin e-based inhibitors. Although their cytotoxic and cytostatic potential has b een proven, they are not likely to replace standard chemotherapy regimens a s single-agent, first-line therapeutics. Instead, their promising additive and synergistic antitumour effects in combination with standard chemotherap eutics suggest that these novel agents will find their greatest utility and efficacy in conjunction with existing anticancer agents.