AntiEGFR作用机制.ppt

* * - The epidermal growth factor receptor (EGFR) is a transmembrane receptor with an intracellular tyrosine kinase domain, which is activated by growth factors. The main activating ligands are epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha).[1] - EGFR is a proto-oncogene and its activation plays a key role in the development of many cancers.[2] Activation occurs because of gene amplification, gene mutation and/or autocrine stimulation due to the overproduction of the EGFR ligands (e.g. EGF and TGF-alpha). Activation leads to the pairing of receptors with either another EGFR (homodimers) or another member of the EGFR family (heterodimers).[1] - Receptor dimerization initiates an intracellular signaling cascade, gene activation and the stimulation of cell cycle progression.[1] 1. Baselga J. Eur J Cancer 2001; 37 Suppl 4:S16–S22. 2. Yarden Y, Sliwkowski MX. Nat Rev Mol Cell Biol 2001; 2:127–137. * - The EGFR intracellular signaling cascade stimulates cell proliferation, angiogenesis, cell migration and metastasis formation and also provides protection from apoptosis and prevents the loss of differentiation (ie all the key processes involved in tumorigenesis).[1] - EGFR is expressed in a high proportion of solid tumors, in particular head and neck, lung and colorectal cancer.[2] Expression has been correlated with disease progression.[3] Many studies have shown that EGFR expression can be an adverse prognostic factor for cancer treatment outcome.[2] - ‘Evidence for a role for the EGFR in the inhibition and pathogenesis of various cancers has led to the rational design and development of agents that selectively target this receptor’.[3] 1. Baselga J. Eur J Cancer 2001; 37 Suppl 4:S16-S22. 2. Nicholson RI, Gee JMW, Harper ME. Eur J Cancer 2001; 37 Suppl 4:S9-S15. 3. Baselga J. The Oncologist 2002; 7 Suppl 4:2-8. * - Expression of EGFR has been observed in a variety of human tumors, both in vitro and in vivo.[1-15] The increased leve