Receptor tyrosine kinases (RTKs) represent the largest class of cellular receptors. The extracellular ligand-binding domain of these proteins transmit signals through its transmembrane segment to regulate critical functions such as proliferation, apoptosis, and differentiation via its intracellular tyrosine kinase domain. The epidermal growth factor receptor (EGFR; erbB1) represents one fraction of the diverse RTK family. Other members of the RTK family includes HER2/neu (ErbB2), erbB3, and erbB4. 1–3
RTK family members are characterized by the variety of receptor-specific ligands and signaling pathway intermediates which promote transduction. The specific ligands that bind to EGFR are epidermal growth factor (EGF), transforming growth factor-a (TGF-a), amphiregulin, epigen, betacellulin, heparin-binding EGF, and epieregulin.1,3–5 Following binding of either of these ligands to EGFR, the receptor forms either a homo- or heterodimeric complex activating the receptor’s tyrosine kinase domain.2,3 The enzymatic activity of EGFR phosphorylates and thereby activates intracellular proteins and regulates transcription.6 EGFR transduction is most commonly mediated by three major signaling pathways:
- The Ras-Raf-MAP kinase pathway,7
- The phosphatidylinositol 3-kinase (PI-3 K) and Akt pathway,8
- The stress-activated Jak/Stat and protein kinase C pathway.1,9
Pathophysiology and Therapeutics
In contrast to the maintenance of cellular homeostasis within normal tissue, EGFR also promotes malignant transformation and tumor growth via dysregulation of apoptosis, cellular proliferation, promotion of angiogenesis, and metastasis. Aberrant activation of ErbB receptors are attributed to:
- Receptor overexpression,10
- Mutant receptors resulting in ligand-independent activation,10,11
- Autocrine activation by overproduction of the ligand,12
- Ligand-independent activation through other receptor systems such as the urokinase plasminogen receptor.1,13
In regards to EGFR therapeutic targeting, these modes of aberrant activation are vulnerable to:
- Monoclonal antibodies against the EGFR,9
- Inhibition of the receptor tyrosine kinase domain,14
- Inhibition of receptor trafficking to the cell membrane,15
- Inhibition of EGFR synthesis through antisense oligonucleotides.16
Examples of tyrosine kinase inhibitors (TKIs) include erlotinib and gefitinib that reversibly inhibit the EGFR tyrosine kinase domain by competitively binding w/ATP. The monoclonal antibodies, cetuximab (a chimeric mouse-human IgG1 ab) and panitumumab (a fully humanized IgG2 ab), block ligand binding to the extracellular domain of EGFR, promote receptor internalization, and mediate cytotoxicity. In advanced non-small cell lung cancer (NSCLC), chemotherapy results in a median overall survival (OS) of 8 to 12 months and a median progression-free survival (PFS) of 5- 6 months. 17–19 When TKIs, gefitinib or erlotinib, are used the response rates of OS and PFS increased to 20 -30 months and 10 – 14 months, respectively. 19–23
Despite identification of several independent therapeutic strategies, investigators have discovered an assortment of mechanisms in which EGFR is further modified to continue malignancy despite the previously described standard-of-care. Therefore, the current therapeutic outlook is increasingly dedicated to characterizing and targeting the mechanism of resistance and increasing the disease-free survival of patients. The overall resolution thus far to such objective has been to combine classic chemotherapy, with current advanced targeted therapies as an attempt of “complete” medicine.24 .
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