Ever since the beginning of our awareness of growth factors in the early 1960’s by Stanley Cohen and Rita Levi-Montalcini, EGF (Epidermal Growth Factor) has been in the forefront of medical science. EGF, along with the EGF Receptors (EGFR), has been implicated in a number of cancer types for decades, although the exact pathway has been elusive. Scientists know that that the interaction between EGF and EGFR creates an intracellular signaling cascade that affects many other growth factors, including FGF2 (Fibroblast Growth Factor 2), IL8 (Interleukin 8) and VEGF (Vascular Endothelial Growth Factor). But that’s also precisely the reason that researchers have had so much trouble pinning down the implicit role that EGFR has on cancer development and proliferation.

EGF is only the founding member of a family of proteins that bear its name. There are 13 known EGF family members, including TGF-α (Transforming Growth Factor-α) and HB-EGF (Heparin Binding EGF-like Growth Factor). EGF family members can be characterized by their association with EGFR. There are 4 EGFRs, which all have multiple names. We will settle on calling them ErbB1, ErbB2, ErbB3 and ErbB4. Of these, ErbB2 does not bind to any of the EGF ligands. Instead, ErbB2 is activated only as a consequence of homodimer formation with one of the other three EGFRs.

Recently, Seshacharyulu et al (2012) published a comprehensive review of EGFRs and the various therapeutic treatments that are currently being investigated that is well worth the read. There are two therapeutic approaches currently being employed: monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKIs). Monoclonal antibodies are specifically designed to be directed against the extracellular region of EGFR, creating a ligand competitive inhibition (Burgess, 2003). These antibodies then induce receptor internalization, ubiquitinization, degradation and prolonged downregulation (Sunada, 1986). TKI’s exist as adenosine triphosphate (ATP) analogues and inhibit EGFR signaling by competing and binding with ATP binding pockets on the intracellular catalytic kinase domain of receptor tyrosine kinases (RTKs) (Seshacharyulu, 2012). There are two types of TKI: Reversible inhibitors, which compete with ATP molecules, and Irreversible inhibitors, which bind to kinase active sites covalently (prolonging their effects and decreasing the need for frequent dosing).

Seshacharyulu et al reviewed several of the ongoing cancer therapeutic treatments in their article, including the monoclonal antibodies Cetuximab and Panitumumab as well as the TKIs, Gefitinib, Erlotinib, Lapatinib, and a new generation TKI called Canertinib. Ultimately, the reviewers believe that irreversible TKIs have the best opportunity for cancer treatment, but the risk is that they tend to have too much non-specificity and TK point mutations can easily lead to resistance. But the combined use of a chemotherapeutic TKI with a chemopreventive agent can potentially have an adjuvant action by inhibiting transcriptional factors and intercepting the autocrine loops generated by the activation of EGFR (Seshacharyulu, 2012).

To read the full free article, go to Seshacharyulu et al (2012) on Pubmed. And for questions on EGF or any of GoldBio’s other growth factors, just email us at techsuppor@goldbio.com.

Seshacharyulu, P., Ponnusamy, M. P., Haridas, D., Jain, M., Ganti, A. K., & Batra, S. K. (2012). Targeting the EGFR signaling pathway in cancer therapy. Expert opinion on therapeutic targets, 16(1), 15-31.

Burgess, A. W., Cho, H. S., Eigenbrot, C., Ferguson, K. M., Garrett, T. P., Leahy, D. J., ... & Yokoyama, S. (2003). An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Molecular cell, 12(3), 541-552.

Sunada, H., Magun, B. E., Mendelsohn, J., & MacLeod, C. L. (1986). Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation. Proceedings of the National Academy of Sciences, 83(11), 3825-3829.

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