Epidermal growth factor receptor (EGFR), its family members Her-2/ErbB-2, Her-3, Her-4 and their ligands, are involved in over 70% of all cancers. EGFR itself has been implicated in ~30% of all solid human tumors. EGFR is associated not only with the proliferation of tumor cells, but also with enhanced tumor cell survival, angiogenesis and metastatic spread. The enhanced activity of the EGFR due to over-expression, co-expression of the receptor and its ligands, as well as activating mutations is the hallmark of many human carcinomas.

The co-expression of the EGFR and its ligands, especially TGFα and EGF, plays a key role in EGFR-mediated tumorigenesis. EGFR expression is a prognostic indicator, predicting poor survival and indicating an advanced state of the disease. When EGFR is co-expressed with other members of the Her family, the various combinations of Her dimers confer different degrees of malignancy. It has been noted that the co-expression of EGFR with Her-2 and Her-3 is associated with more aggressive clinical behavior. In many types of tumor, including lung, breast, prostate, ovary, gastrointestinal tract and brain, the EGFR receptor is expressed approximately 100 times the normal number of EGF receptors found on the surface of normal cells. Furthermore, expression of high levels of these two receptors in nonmalignant cell lines, either alone or in combination, leads to a transformed phenotype.

Due to all these observations, it is no surprise that EGFR and Her-2/Erb-2 were identified early on as important targets for drug development. Indeed, the first signal transduction therapeutic agent introduced into the clinic was Herceptin, an anti-Her-2 antibody, followed closely by the protein tyrosine kinase inhibitors Iressa (ZD 1839) and Tarceva (OSI-774) and the anti-EGFR antibody Erbitux (mAb 225).

The enhanced activity of the EGFR is due to a number of molecular events. Most common is the overexpression of the receptor along with the expression of the EGFR receptor ligands like TGFα, EGF, amphiregulin and HB-EGF, leading to persistent autocrine stimulation. Another common occurrence is an activating mutation resulting from deletion of exons 2 through 7, leading to a persistently active receptor Δ (2-7)EGFR (also known as EFFRvIII) in the absence of a ligand. The emergence of this mutation occurs in the most aggressive forms of EGFR overexpressing tumors.

Activation of the EGFR pathway is not limited to members of the EGFR family, but frequently occurs due to the transactivation by other signaling pathways such as mitogenic G protein-coupled receptors and the PDGF receptor. Furthermore, the EGFR pathway cooperates in a synergistic manner with pp60c-Src, and the deletion of PTEN, the negative regulator of PKB/Akt. The frequent involvement of EGFR in human tumors has identified it as a target for novel therapies. The first breakthrough was the development of selective EGFR kinase inhibitors (tyrphostins) like tyrphostins, AG 1478 and ZD 1839 (Iressa). Iressa is one of the two kinase inhibitors (the other being Gleevec) to receive approval for clinical application. It is important to note that it was recently found that the response of patients suffering from non-small-cell lung carcinoma to Iressa, is limited to the 7-10% harboring mutations in the kinase domain of the receptor. Other inhibitors, similar to Iressa, like Tarceva (OSI-774), the pan-Her reversible inhibitor GW 2016, the irreversible inhibitor CI-1033, which targets both RGFR and Her-2, are in the pipeline. Antibodies to the EGFR, like Erbitux and TGFα fused to a mutated form of pseudomonas exotoxin, TP-38, have also undergone clinical development.

The Table below contains accepted modulators and additional information.

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