Receptors and Inhibitors | Biowire Spring 2011



Biowire Spring 2011 — Cell Lines — Models of Disease

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Epidermal growth factor receptor (EGFR) is a principle member of the receptor tyrosine kinases (RTKs) family of cell-surface growthfactor receptors. Its members include EGFR (ErbB1 or HER1; Product Nos. E3641 and E2645), HER2/neu (ErbB2), HER3 (ErbB3), and HER4 (ErbB4)1. Specific growth factors activate the ErbB family of receptors (Table 1) and, of these, seven have been shown to activate EGFR2. RTKs have intrinsic intracellular protein tyrosine kinase (TK) activity triggered by sequential ligand binding and receptor dimerization. Activation of EGFR leads to autophosphorylation of several tyrosine residues in the C-terminal domain eliciting downstream activation of signaling proteins. These proteins associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domains to initiate several signal transduction cascades3. Principal among these are the MAPK, PI3K/Akt, and JNK pathways, which regulate cell growth, differentiation, and cytoskeletal changes4. Aberrant overexpression or activation of the EGFR is known to play a major role in cancer cell proliferation, survival, invasion, and tumor angiogenesis5. Thus EGFR is an important target for biomedical studies and clinical oncology6.

Table 1. The ErbB Protein Family 

Table 1. The ErbB Protein Family


There are numerous therapeutic approaches aimed at the EGFR (Table 2). These include using select monoclonal antibodies to block the extracellular ligand-binding domain and prevent ligand-mediated activation, and bioactive small molecules to block various domains of the receptor, including the intracellular EGFR tyrosine kinase. Without kinase activity, EGFR is unable to activate itself, which is a prerequisite for binding of downstream adaptor proteins. In addition to clinical applications, synthetic small molecules are used as research tools. The most prominent among them are the ATP-binding site-selective inhibitors. Both CP-380736 and PD158780 are potent and selective inhibitors of EGFR tyrosine kinase. PD158780 is a potent, cell-permeable, reversible ATP-competitive inhibitor of EGFR tyrosine kinase activity with IC50 values of 0.008, 49, and 52 nM for EGFR, ErbB2 (HER2), and Erb4 (HER4), respectively. A number of natural occurring products have also been discovered that interact non-specifically with the EGFR tyrosine kinase. A couple examples include Butein (Product No. B178), a chalcone found in Lacquer tree Toxicodendron vernicifluum and Curcumin (Product Nos. C7727 and C1386), the principal curcuminoid of the spice turmeric Curcuma longa.

Table 2. Therapeutic Inhibitors of EGFR 

Table 2. Therapeutic Inhibitors of EGFR


Recently, mounting resistance to small molecules targeting the EGFR has spawned research into the development of dual- and multiple-specificity inhibitors targeting multiple members of the ErbB family at once. For example, GW2974 is a dual-specificity kinase inhibitor of EGFR and ErbB2 and functions by blocking the phosphorylation of the EGFR or ErbB2 kinase domain with IC50 values of 16 nM and 6 nM, respectively7. While targeting multiple members of the ErbB family is a viable approach, the complexity of the EGFR signaling cascade itself increases the number of proteins that can be targeted for the development of pathway-specific drugs. This effectively provides numerous targets for the development of dual-specificity inhibitors. Generation of small molecules that target individual components of the cascade enables combination drug therapy approaches, and such an approach might prevent selection and survival of intrinsic or acquired resistance mutants8.

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References

  1. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141:1117–34.
  2. Linggi B, Carpenter G. ErbB receptors: new insights on mechanisms and biology. Trends Cell Biol. 2006;16:649–56.
  3. Downward J, Parker P, Waterfield MD. Autophosphorylation sites on the epidermal growth factor receptor. Nature. 1984;311:483–85.
  4. Oda K, Matsuoka Y, Funahashi A, et al. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol. 2005;1:2005.0010.
  5. Zwick E, Bange J, Ullrich A. Receptor tyrosine kinase signalling as a target for cancer intervention strategies. Endocr Relat Cancer. 2001;8:161–73.
  6. Zhang H, Berezov A, Wang Q, et al. ErbB receptors: from oncogenes to targeted cancer therapies. J Clin Invest. 2007;117:2051–58.
  7. Rusnak DW, Affleck K, Cockerill SG, et al. The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Res. 2001;61:7196–203.
  8. Wheeler DL, Dunn EF, Harari PM. Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Nat Rev Clin Oncol. 2010;7:493–507.

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