EGFR signaling and drug discovery.pdf

Fax +41 61 306 12 34 E-Mail karger@karger.ch Review Oncology 2009;77:400–410 DOI: 10.1159/000279388 EGFR Signaling and Drug Discovery Georg Lurje a Heinz-Josef Lenz b, c a Department of Visceral- and Transplantation Surgery, University Hospital Zurich, Zurich , Switzerland; b Division of Medical Oncology and c Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, Calif. , USA Introduction Normal cell growth is tightly regulated through acti- vation of cellular signal transduction pathways. Growth factors and their receptors play a fundamental role in the communication between outside the cell surface and the inside compartments [1, 2] . The human epidermal growth factor receptor (ErbB/HER) family comprises four close- ly related receptors: epidermal growth factor receptor (EGFR; HER-1, and ERBB1), human EGFR-2 (HER-2 and ERBB2), HER-3, and HER-4, which are transmembrane glycoproteins containing an extracellular ligand binding domain and an intracellular receptor tyrosine kinase (RTK) domain. Dysregulation of ErbB/HER pathways by overexpression or constitutive activation can promote tu- mor processes including angiogenesis and metastasis and is associated with poor prognosis in many human malig- nancies [3, 4] . In addition, it is well recognized that mem- bers of ErbB/HER share remarkable homology in their TK domains, but are distinct in their extracellular and COOH-terminal domains [5] . In fact, ERBs are made up of an extracellular region (ectodomain), which contains approximately 620 amino acids, a short hydrophobic transmembrane region, and a cytoplasmatic TK domain (endodomain) [6–8] . The extracellular region of each family member comprises up to four subdomains, L1, CR1, L2, and CR2, where ‘L’ signifies a leucine-rich re- peat domain and ‘CR’ a cysteine-rich region. Interesting- Key Words Drug discovery  Epidermal growt