Introduction of the structure and mechanism of EGFRvIII rabbit monoclonal antibody

So, what does EGFRvIII have to do with it?

The simple image says: EGFR is a type of cell commander, responsible for regulating the normal growth of cells. If the command and regulation of the scorpion is a signal regulation disorder, it will lead to a variety of tumors. The cells responsible for regulation by EGFR are cells in the tissue of epithelial origin.

However, EGFR is somewhat arrogant and has many mutant forms. The most common mutation in the extracellular region is EGFRvIII. It is mainly annoying that the gene is too heavy to be smashed, that is, 801 bases are removed between the exons 2-7 of the coding region, and 267 amino acids are missing from the wild type in the extracellular region. A fusion region and a new glycine residue (Fig. 1) were created between the 1 and 8 receptors, which is a tumor-specific in-frame deletion mutation. Compared to wild type, EGFRvIII is constitutively activated, independent of ligand. This mutation is found in a variety of cancers (such as breast cancer, lung cancer, head and neck cancer, etc.), but is most common in blastomas.

Figure 1. Schematic diagram of EGFRvIII structure

Glioblastoma and EGFRvIII

Primary GBM often has EGFR mutations compared to secondary GBM (generally derived from low-level precursors). This is also the most common type of clinical disease, and an epidemiological survey shows that up to 95% of cases are primary GBM.

Recent studies of complete exome sequencing and DNA copy number analysis of 251 primary GBMs provide a global overview of the corresponding genetic changes in receptor tyrosine kinases. The results showed that 67.3% of GBM had genetic variation in RTK, and 57.4% of GBM had EGFR variation.

In addition, other studies have found that 50% of patients with EGFR expansion have an EGFRvIII mutation. Approximately 20-30% of GBM has an EGFRvIII mutation . A retrospective analysis of a clinical study showed that in 40 patients with EGFR expansion, the survival of patients expressing EGFRvIII (0.839 years) was significantly less than that of patients without expression (1.374 years, p=0.0031).

A number of drugs targeting this mutation have entered clinical trials, and in the first half of this year, Celldex's Rindopepimut received FDA breakthrough therapy approval for approval of EGFRvIII-positive GBM.  

Figure 2. Genetic variation of receptor tyrosine kinases in primary GBM

EGFRvIII signaling pathway

It is precisely because EGFRvIII is often co-expressed with wild-type EGFR, especially in tumors overexpressing EGFR, which makes it more difficult to understand its role in tumorigenesis.

Studies have found that transformation occurs intracellularly, and phosphorylation of EGFRvIII and increased signaling of downstream STAT are dependent on EGFR. There is also evidence that EGFRvIII is internalized in GBM and forms a carcinogenic complex with STAT3. The GBM cell line transfected with EGFRvIII has a distinct growth advantage over the cell line containing wild type EGFR. This change is thought to be caused by a decrease in apoptosis due to an increase in proliferation rate. Several signaling pathways such as PI3K/Akt, Ras/Raf/MAPK, STAT3 and NFkB are involved in the cancer-promoting effect of EGFRvIII (Fig. 4).

Similar to the EGFR signal, EGFRvIII also activates the RTK/RAS/PI3K pathway. This will increase the level of phosphorylated AKT while reducing the P27 content. Recent studies have found that EGFRvIII activates mTORC2, which in turn leads to activation of the NFkB pathway and tolerance to chemotherapy. Similarly, EGFRvIII-selective activation of the PI3K/Akt pathway is also thought to mediate the tolerance of EGFRvIII-positive GBM to radiation therapy. Several studies have shown that EGFRvIII also promotes the carcinogenicity of GBM along with the Src family of kinases. Expression of EGFRvIII leads to the activation of receptor-activated phosphorylation, which then leads to tumor growth and migration following binding to Src and Tyn. VEGFvIII promotes GBM also in its promotion of tumor angiogenesis.

Multiple studies have shown that transfection of EGFRvIII in GBM cells increases IL-8 levels. Recent studies have also found that EGFRVIII induces the expression of SOX9 and FOXG1 and promotes tumorigenesis by remodeling the transcription factor network and the epigenetic genome.

Figure 3. Downstream signaling pathway of EGFRvIII  

references:

1. Current Therapeutic Advances Targeting EGFR and EGFRvIII inGlioblastoma. Front Oncol. 2015 Jan 29;5:5.

2. EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progress in glioblastoma. Cancer Cell. 2013 Oct 14;24(4):438-49.

3. EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling. Mol Cell. 2015 Oct 15;60(2):307-18.

4. Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma. Nat Rev Cancer. 2015 May;15(5):302-10.

5. Rindopepimut: an evidence-based review of its therapeutic potential in the treatment of EGFRvIII-positive glioblastoma. Core Evid. 2012;7:93-103.

6. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J. 2013Nov;280(21):5350-70.

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