EGFR INHIBITORS VERSUS CANCER

Introduction: The HER family of proteins

Recently collated and renamed as a single family of homologous series of proteins the HER family represents a major group of cellular membrane signal transmitters. Confusingly in literature the new naming system is inconsistently followed and the four HER receptors are often referred to as EGFR (HER1; ErRB1), ErRB2 (HER2), ErRB3 (HER3) and ErRB4 (HER4). These receptors have a very specific mode of action in that extracellular ligands can bind to the surface receptor domains on the cell membrane. Binding to any one of four different versions the ligand can stimulate a number of possible responses. Upon binding, the complex formed will alter conformationally and dimerize with another HER receptor increasing the number of permutations possible in the signaling process. The Dimerization initiates changes in the conformational state of the protein that induces the intercellular segment of the protein to reveal binding domains previously hidden. The protein will auto-phosphorylate activating it to receiving intercellular protein binding which starts the signaling process with the cell. The number of pathways that can be activated in different ways is large leading to contradictory responses.

The Mutation of the HER family

In numerous cancers, the tumors have been analyses for expression factors and activity profiles for many receptor types. The protein expression describes the presence or abundance of a protein but activity denotes whether it is functional or not. Activity and expression do not necessarily have to agree with each other. Over expression of EGFR is commonly found in tumors, most notable Lung cancer (NSCLC) but sometimes activity is not. In other tumors EGFR activity can be in condition of permanent activity but the actual expression could actually be low. The reason behind these considerations is whether the protein formed is correctly encoded during gene transcription. Using NSCLC cell lines many different mutations have been isolated in the EGFR gene encoding, although only a few seem to have significance. The most mutations observed in the clinical setting are for the Exon 21 (L858R) and the Exon 19 deletions, these two mutations make up 90% of all seen. In addition there are T790M, G719X and S7681 making a minor proportion of the remaining observed, where the T790M (exon 20) alone makes up 3% of the total. Most of the 7% not covered by L858R and the Exon 19 deletion are situations where two mutations exist and these are most commonly the T790M+Exon 19 or T790M+L858R combinations.

Inhibition of the HER family

Inhibitors of the HER family of proteins can be classified into two groups, those consisting of small molecules built around a structurally similar core sequence and those consisting of monoclonal antibodies specific for the HER1-4 domains. The monoclonal antibodies target the extracellular domains of the HER family blocking the binding of the ligands to the receptor, in addition these antibodies can stimulate the receptor to be degraded or to transfer to intracellular activity. The second group of inhibitors work by being internalized into the cell and competitively binding to the tyrosine kinase domain with regard to ATP. Upon binding to the magnesium-dominated pocket, the natural ligand cannot then trigger signaling processes. Some inhibitors are reversible such as Erlotinib or Gefitinib but most of the more recently introduced molecules irreversibly bind to the domain inactivating the receptor.

EGFR Inhibitors

With the development of the EGFR specific inhibitors Gefitinib and ErlotinibEGFR inhibition was demonstrated to be clinically viable. In addition, there are small molecule EGFR antagonists such as Lapatinib or Vandetanib as well as developmental compounds AEE788 or AP26113. EGFR inhibitor drugs can be specific for HER1 or multi-targeted against HER1-4 or even against a very different pathway such as the EGFR kinase inhibitor AP26113, which inhibits equally the ALK pathway, as well as EGFR. Other EGFR pathway inhibitorsinclude Cetuximab, which is one of the first monoclonal antibody therapies developed, Panitumumab, the first fully human derived moncolnal antibody,theEGFR selective inhibitor Matuzumab and the EGFR agonist Zalutumumab.EGFR inhibitors in clinical trials that have been running for several years are being demonstrated to be effective in sub sections of the population group. Screening of patients for mutations and crosslinking this to sensitivity is becoming more common placed

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