The Epidermal Growth Factor Receptor Family of Tyrosine Kinases and Cancer: Can An Atypical Exemplar Be A Sound Therapeutic Target?

Abstract

Abstract: Epidermal Growth Factor (EGF) receptor was the first peptide growth hormone receptor found to contain an intracellular tyrosine kinase. It is frequently used to exemplify the properties of the whole family of receptor tyrosine kinases. Much work has been done on EGFr to elucidate the mechanisms of activation of RTKs, and their coupling to downstream signaling processes. The type I RTKs consist of four closely related RTKs, and a bewildering number of ligands. The number of ligands is not typical for RTKs, but the discovery that this family can form signaling-competent heterodimers as well as homodimers may explain this abundance. The type I RTKs are almost ubiquitous in solid neoplasias, as 90% of clinical samples express at least one family member, and at least 60% of tumours overexpress at least one of the receptors or cognate growth factors. Overexpression correlates with poor prognosis and shorter survival times. The high prevalence suggests that type I RTKs may activate more transforming signaling pathways that most other RTKs. Both the high prevalence, and the importance of the EGFr family to the transformed phenotype, suggest that inhibition of their signaling will have therapeutic utility. This has been investigated by finding blocking antibodies for the ligand binding domains of the receptors, enzyme inhibitors for the tyrosine kinases of the family and inhibitors of downstream signaling. The enzyme inhibitor approach has led to small molecule enzyme inhibitors of great potency and selectivity for the EGFr tyrosine kinase.