ReviewMechanisms for oncogenic activation of the epidermal growth factor receptor
Introduction
Carcinogenesis is a multi-step process that requires the accumulation of several genetic alterations in a single cell. Among numerous factors, carcinogenesis involves the activation of oncogenes such as the epidermal growth factor receptor (EGFR), also known as ErbB1/HER1. EGFR is a receptor tyrosine kinase (RTK) that is catalytically active and under tight regulatory control. This receptor belongs to the ErbB/HER family of ligand-activated RTKs, which in addition include ErbB2/Neu/HER2, ErbB3/HER3 and ErbB4/HER4 [1]. EGFR and its family members play essential roles in regulating a number of cellular processes including cell proliferation, survival and migration [2]. Dysregulation of their activity is therefore strongly associated with tumorigenesis, which classifies them as some of the most frequent implicated cell-surface markers of human cancer [3].
The involvement of increased and/or aberrant EGFR activity in human cancers is well documented [4], [5], [6] and cancer patients with altered EGFR activity tend to have a more aggressive disease, associated with a poor clinical outcome [1]. Therefore, EGFR is a rational target for anti-tumor strategies. There is a range of mechanisms leading to dysregulated EGFR activity and it is important to know which one is prevalent in a particular tumor in order to give the patients the most appropriate treatment.
Since the vast majority of reviews largely focus on anti-EGFR agents and their clinical outcome, this review will mainly focus on the mechanisms by which EGFR becomes oncogenic and briefly summarize some of the clinical approaches currently used to target tumors with aberrant EGFR activation. A detailed molecular and genetic understanding of how EGFR contributes to the malignant phenotype is important for future design and development of tumor-specific anticancer approaches.
Section snippets
EGFR: structure and regulation of activity
The EGFR is a highly glycosylated 170 kDa membrane spanning protein, which consists of a single polypeptide chain of 1186 amino acids [7], [8], [9]. Like all RTKs, the EGFR is characterized by three main domains: an extracellular ligand-binding domain, a transmembrane domain and a cytoplasmic domain containing the tyrosine kinase (Fig. 1A) [1], [10]. The extracellular domain of the EGFR can be further divided into four subdomains designated I, II, III and IV (Fig. 1A). Crystallographic studies
EGFR and cancer: mechanisms leading to the constitutive activation of EGFR
As EGFR is involved in the regulation of cell proliferation, motility and survival an imbalance in the EGFR-ligand system giving rise to increased EGFR signaling can lead to neoplastic transformation. Indeed, dysregulated EGFR has frequently been found in various forms of human cancers [19], [20].
There are quite a few mechanisms by which the tight regulation of the EGFR-ligand system can be abrogated (Fig. 2). These include: 1) increased production of ligands, 2) increased levels of EGFR
Conclusion
EGFR has been intensively studied as a therapeutic target. New agents are entering the clinic and new combinatorial approaches with anti-EGFR agents are being explored. Ongoing clinical trials continue to investigate EGFR therapeutics in various treatment settings and major efforts are being made to identify molecular markers that can select patients more likely to respond to anti-EGFR therapy. However, as EGFR therapeutics have so far only been partially successful, it is important to have a
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