Introduction: The EGFR’s role in the HER pathway

A major pathway in the regulation of cell growth / death is the HER pathway, this pathway consists of four structurally related proteins primarily located in the cell membrane. The family members consist of HER1 (also known as EGFR), HER2 (also known as ErbB2), HER3 (also known as ErbB3) and HER4 (also known as ErbB4) [1-4]. These receptors consist of an extracellular head and an intracellular tail lying across the cell membrane. Ligands binding to the extracellular receptor induce conformational changes which reveal binding domains within the intracellular tail. Auto-phosphorylation of the tyrosine kinase domain is a result of the HER receptor forming dimers and depending on which of several different ligands induced the change the tail section attracts proteins to initiate signaling cascades to the nucleus [5]. Ligands that trigger this signaling pathway consist of endothelial growth factor (EGF), transforming growth factor alpha (TGFα), beracellulin (BTC), epiregulin (EPR) and amphiregulin (AREG) [1;6;7]. One of the most researched downstream pathways of the HER family protein is EGFR (HER1). Signaling from EGFR triggers any one of four different pathways:- the PI-3K pathway consisting of PI-3K/Akt/Aktα and PI-3K/PKC/NFκB; the Ras pathway consisting of GrB2-SOS/Ras/Raf/MEK where MEK can activate one three possible responses (MEKK, MAPK and MKK); the JAK pathway consisting of JAK/STAT3or 5; the PLCγ pathway consisting of PLCγ/PIP2/IP3/DAG. These pathways all regulate gene transcription and cellular proliferation as well as normal apoptotic processes.

The HER1 receptor is found in nearly all tissue and is frequently found to be over expressed in a variety of cancer types. One of the prognosis factors for a poor response to chemotherapy is the translocalization of the HER1 receptor to the nuclear membrane. Here the activated HER1 affects cyclin D1, iNOS, BMyb and DNA repair bringing about either G1/S proliferation, migration (metastasis) or radioresistance [2;3;8-10]. With the EGFR structure lying extra-cellularly EGFR inhibition was therefore considered to be an attractive target for the treatment of many proliferation / differentiation based diseases. The development of small molecule EGFR antagonists and EGFR agonists open a new avenue of treatment for previously resistant diseases.


Inhibition of EGFR:

EGFR inhibitors mainly consist of small molecules antagonists based on quinazolines [11] or anti-EGFR monoclonal antibodies agonists (consisting of a murine antibody transfected with human genetic information) [7;12;13]. The most advanced monoclonal antibody available (bevacizumab) is approved by the FDA for treatment in chronic renal cell carcinoma in combination with irinotecan [14-16] as well as for HNSCC in combination with radiation and as a single therapy for patients whom platinum treatment failed [17-19]. Monoclonal antibodies inhibit EGFR by binding to the extracellular receptor site preventing activation by extracellular factors. EGFR pathway inhibitors inhibit EGFR by competing with endogenous ligands (ATP) for binding to the protein, in this way EGFR is prevented from initiating a signal cascade. These EGFR kinase inhibitors of which Erlotinib, Gefitinib or Laptinib represent but a few of the many available, have been shown to be effective in only a small proportion of the cancer population, those possessing mutations in the EGFR tyrosine kinase domain. This limitation has led to Gefitinib approval being withdrawn in regard to first line treatment in lung cancer and limited it to only those patients enrolled in current clinical trials.

EGFR Inhibitors: Clinical status

With the development of fast and accurate EGFR assays it is possible to screen patients of a particular type from the general cancer population. Optimization of EGFR specific inhibitors fine tune the treatment profile for these EGFR inhibitor drugs, however this procedure is still in its infancy and much work needs to be performed to establish set protocols [20-23]. As has already been indicated there are several EGFR inhibitors approved for clinical use (Gefitinib, Erlotinib, Lapatinib, Bevacizumab and Cetuximab. In addition there continues a strong presence of EGFR inhibitors in clinical trials increasing the range of their use and optimiszing their effects. Examples of this are the EGFR selective inhibitors focusing on the KRAS and T790M mutations in lung cancer. Afatinib, Necitumumab and Nimotuzumab are all EGFR inhibitors in lung cancer phase III development while at Phase I/II level there is PF299804, RO5083945, ABT-806 and AP26113.



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