Pathophysiology of EGFR and options of targeting

The family of human epidermal growth factor (HER) receptors representing transmembrane receptor kinases consists of the epidermal growth factor receptor (EGFR; HER-1), HER-2, HER-3 and HER-4, respectively. Several soluble ligands of the epidermal growth factor family induce formation of HER receptor homodimers or heterodimers leading to autophosphorylation of tyrosine residues within the cytoplasmatic catalytic kinase domain of the receptor. Interestingly, HER-2 is the preferred recruited heterodimerization partner despite the fact, that it does not bind to any known ligands of the HER family. In the complex with EGFR, HER-2 potentiates EGFR signaling by enhancing the binding affinity of its ligand EGF, reducing its degradation and predisposing the receptor to recycling. HER receptors activate numerous downstream pathways in response to extracellular ligand-binding including cell differentiation, proliferation (MAPK), migration and survival (PI3K). Dysregulation of HER mediated cellular pathways has been implicated in the carcinogenesis of breast cancer. Especially amplification of the HER-2 gene with consecutive overexpression of the HER-2 receptor, found in 25–30% of all breast cancer cases is associated with the aggressive basal cell like tumor type and significantly shortened survival and specific resistances against certain types of cytotoxic and endocrine agents.

EGFR, a 170 kDa protein, is present in many cell types. The hyperactivation of EGFR dependent pathways in tumors is due to three different mechanisms: first, overexpression of the receptor itself, second, autocrine production of ligands, esp. EGF and TGFα and third mutations within the receptor. Just recently a mutation called variant III was identified which exhibited a continuously activated EGF signaling pathway. More than 10 ligands are known to bind to EGFR including the above mentioned EGF, TGFα, heparin-binding EGF, amphiregulin and betacellulin. Binding starts a specific cascade of cellular responses. The autophoshorylation process creates binding sites for src-homology 2 and phospotyrosine-binding-domain-containing proteins which serve as adaptors of downstream proteins involved in signal transduction. The oncological significance for EGFR expression was shown in several studies esp. for head and neck, bladder and esophageal cancers. In breast cancer the clinical significance for EGFR is unclear but due to the heterodimerization with HER-2 already a potent target in tailored therapeutic approaches.

So far there are two distinct inhibition strategies in regards to HER mediated pathways in cancer, monoclonal antibodies (mAb) and tyrosine kinase inhibitors (TKI), respectively. For the mAb approach there is the very successful story of Trastuzumab, specifically directed against the extracellular domain of HER-2, with high response rates in metastatic breast cancer and already routinely used in HER-2 overexpressing primary breast cancer. The precise mechanism by which the antibody exerts its activity is not known which makes it even more difficult to understand the observed Trastuzumab resistances. Redundant signaling pathways, e.g. insulin-like growth factor (IGF), deficient expression of the PTEN tumor suppressor gene and the expression of a highly active truncated isoforms of HER-2 have been so far proposed.

A different antireceptor strategy is given by small-molecule inhibitors which compete with ATP for the ATP binding domain in the intracellular portion of the HER receptor tyrosine kinases and therefore blocking HER activity and downstream MSPK signalling. Several clinical relevant EGFR-selective agents were already successfully tested in different tumor entities, e.g. erlotinib and gefitinib, however these substances failed to show significant effects in breast cancer. In contrast, the bivalent, EGF/HER-2 specific lapatinib demonstrated in different studies significant clinical activity in metastatic breast cancer in combination with cytotoxic agents and is so far the most clinically advanced TKI. Biochemical analyses revealed that lapatinib inhibts HER-2 as well as EGFR phosphorylation with consecutive reduction in the expression of phopho-ERK1/2, phospho-Akt, and cyclin D1. In addition, it increased tumor cell apoptosis. The potential advantages of small molecule inhibitors over antibody directed therapy is given by the oral administration, the ability to pass the blood-brain barrier in the case of brain metastasis, which is more frequently seen in patients under trastuzumab therapy and the chance to outperform trastuzumab related resistance. The latter advantage is given since coepxression of IGF, deficiency of PTEN and a truncated HER-2 does not interfere with the mode of lapatinib activity.

In summary, EGFR represents an interesting target for tailored breast cancer therapy, since HER2 is not an independent partner within the HER family and trastuzumab resistance an emerging problem within the group of HER-2 overexpressing tumors. The development of dual or multiple kinase inhibitors may provide an potential tool to overcome this problematic and further subgroups of breast cancer patients may be defined in the future who might profit from a specific EGFR directed targeted therapy.