egfr

Overview

The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor that plays a role in cell division, cell differentiation and migration.1

  • Ligand binding to EGFR induces receptor dimerization and tyrosine autophosphorylation, which in turn elicits downstream activation and signaling via multilayered and cross-connected pathways and networks.1,2

Implications in cancer

In cancer, EGFR is often mutated, amplified or overexpressed, resulting in abnormal receptor activation. Increased signaling by EGFR contributes to the proliferative nature of the malignant cells.3

  • EGFR-directed therapies have improved outcomes in a number of indications and tumor types.4
    • However, many patients with EGFR-positive tumors fail to respond or develop resistance to EGFR-directed antagonistic therapies due to the complexity of EGFR-signaling.

Oncogenic Expression

Glioblastoma Multiforme

Amplification, rearrangements, and mutations of the epidermal growth factor receptor (EGFR) gene are the most common genetic alterations in glioblastoma (GBM), with amplification occurring in approximately 50% of GBM tumors.3,5 EGFR amplification usually remains unchanged at the time of tumor recurrence.7

  • Grade III histology and EGFR amplification are independent adverse prognostic indicators of IDH-wild type astrocytoma.8

EGFRvIII is the most frequently occurring EGFR mutation in GBM.3,6 The extracellular domain is truncated, resulting in ligand-independent constitutive activity.

  • About 50% of GBMs with EGFR amplification also harbor the EGFRvIII deletion variant (i.e., ~25% of all GBM).9
  • It has been suggested that EGFR amplification and EGFRvIII mutation may correlate with poor prognosis, particularly in younger patients (<60 years of age).3,10
  1. Mendelsohn J, Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol. 2006;33(4):369-385.
  2. Klein P, Mattoon D, Lemmon MA, Schlessinger J. A structure-based model for ligand binding and dimerization of EGF receptors. Proc Natl Acad Sci USA. 2004;101(4):929-934.
  3. Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where the wild things are altered. FEBS Jour. 2013;5350-5370.
  4. Phillips AC, Boghaert ER, Vaidya KS, et al. ABT-414, an antibody-drug conjugate targeting a tumor-selective EGFR epitope. Mol Cancer Ther. 2016;15(4):661-669.
  5. Brennan CW, Verhaak RGW, McKenna A, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462-477.
  6. Zhao LI, Xu KI, Wang SW, et al. Pathological significance of epidermal growth factor receptor expression and amplification in human gliomas. Histopathology. 2012;61:726-736.
  7. van den Bent MJ, Gao Y, Kerkhof M, et al. Changes in the EGFR amplification and EGFRvIII expression between paired primary and recurrent glioblastomas. Neuro Oncol. 2015;17(7):935-941.
  8. Aibaidula A, Chan AK, Shi Z, et al. Adult IDH wild-type lower-grade gliomas should be further stratified. Neuro Oncol. 2017;19(10):1327-1337.
  9. Padfield E, Ellis HP, Kurian KM. Current therapeutic advances targeting EGFR and EGFRvIII in glioblastoma. Front Oncol. 2015;5:5.
  10. Shinojima N, Tada K, Shiraishi S, et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res. 2003;63:6962-6970.

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