ReviewThe EGFRvIII variant in glioblastoma multiforme
Introduction
Since the discovery of the epidermal growth factor (EGF) in 1962 by Stanley Cohen and colleagues,1 tremendous advances have been made in understanding the interaction between growth factors and their accompanying cell surface receptors. One of the most intensely studied classes of receptors has been the ErbB family.2 This family consists of four members, the epidermal growth factor receptor (EGFR, also referred to as ErbB1 or Her1),3 ErbB2 (p185Neu or Her2),4 ErbB3 (Her3)5 and ErbB4 (Her4),6 all of which have been identified to be either over-expressed, amplified or altered in a wide range of human epithelial tumours. All 4 family members share a similar overall structure consisting of an extracellular domain (ECD) with 2 cysteine-rich regions, a single membrane-spanning region and a cytoplasmic domain containing multiple tyrosine residues that are phosphorylated upon ligand binding and receptor activation[7], [8] (Fig. 1). This results in the activation of downstream substrates and the transcription of genes controlling many aspects of cell behaviour such as cell division, survival and cell death, migration and invasion. This review focuses on a tumour-specific variant of the EGFR, the EGFRvIII (EGFR.Δ2-7; de2-7EGFR) and its expression, enhanced tumourigenic potential and clinical relevance in glioblastoma multiforme (GBM).
Primary brain tumours are responsible for about 2% of all deaths from cancer, with high grade gliomas (GBM) being the most common of these tumours.9 Conventional treatment consisting of surgical resection, adjuvant radiation therapy and chemotherapy has had limited success in the treatment of these tumours and there has been little improvement in the median survival of patients with high grade glioma over the past 25 years.10, [11], [12] We will therefore discuss the therapeutic strategies targeting the EGFRvIII receptor that are being investigated as potential treatments for GBM.
Section snippets
EGFRvIII expression in GBM and its functional characteristics
Amplification of the EGFR gene and subsequent over-expression of EGFR protein is the most common genetic alteration in primary GBM, with a frequency of about 40%.[13], [14], [15] Of the GBM that over-express EGFR, 63% to 75% are also found to have rearrangements of the EGFR gene, resulting in tumours expressing both wild-type (wt) EGFR as well as a mutated EGFR.[13], [16], [17], [18], [19] The most common of these EGFR mutations is the EGFRvIII. This mutation has not been observed in normal
EGFRvIII mediated downstream signalling in transfected glioblastoma cell lines confers tumourigenicity
EGFRvIII appears to enhance tumourigenicity through multiple mechanisms (Fig. 2). The GBM cell line U87MG retrovirally transfected with EGFRvIII (U87MG.EGFRvIII; also known as U87MG.Δ2-7, U87MG.ΔEGFR and U87MG-EGFR∗) to co-express wt EGFR and EGFRvIII, showed a significant growth advantage when grown as tumour xenografts and in vitro under serum starvation conditions compared to the parental cell line, which only expresses wt EGFR.[32], [39], [40], [41] This growth advantage is thought to
Pre-clinical data about targeted therapeutics against the EGFRvIII in GBM
The prevalence of EGFRvIII in GBM, the high likelihood that it contributes to many of its malignant features and the lack of normal tissue expression makes it a very attractive therapeutic target. Its role in other tumour types is unclear as there is still debate about whether EGFRvIII is highly expressed and clinically relevant in other tumour types such as lung, prostate, breast and ovarian cancer.56 Many agents that target wt EGFR also target the EGFRvIII, and a few EGFRvIII-specific agents
Clinical trials of EGFR therapeutic agents
To date, clinical trials show that TKIs such as gefitinib and erlotinib, although well tolerated, have only modest activity in unselected patients with gliomas.[82], [83], [84], [85] The response rates for gefitinib in phase II trials of GBM are 0% to 13%[82], [84], 86 and for erlotinib are 0% to 25%87, 88, 89 (Table 1).
A few studies have reported on antibodies raised against wt EGFR as monotherapy in patients with GBM. Neyns et al. report that the use of cetuximab in patients with recurrent
Future considerations in the development of EGFR therapeutics for GBM
Although the development of most agents against wt EGFR or EGFRvIII for the treatment of GBM remains in the early phase, the results thus far have been disappointing despite promising pre-clinical data. One caveat needs to be stated with regards to the latter. Despite multiple studies confirming the frequent occurrence of the EGFRvIII in GBM,[18], [24], [25] attempts to isolate a human cell line naturally expressing this receptor in culture have been unsuccessful.[39], [96], [97] Although not
Conclusions
High-grade gliomas, including GBM, remain a major therapeutic challenge, with poor clinical outcomes with conventional therapies. EGFR amplification and over-expression are common in patients with primary GBM. Associated with this, a substantial number of patients with GBM express the tumour-specific EGFR variant, EGFRvIII. A substantial body of evidence suggests that the EGFRvIII mediates many of the phenotypic features of GBM (particularly high proliferation, invasiveness and low apoptotic
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