Structural insights into the role and targeting of EGFRvIII

Structure. 2024 Sep 5;32(9):1367-1380.e6. doi: 10.1016/j.str.2024.05.018. Epub 2024 Jun 21.

Abstract

The epidermal growth factor receptor (EGFR) is a well-known oncogenic driver in lung and other cancers. In glioblastoma multiforme (GBM), the EGFR deletion variant III (EGFRvIII) is frequently found alongside EGFR amplification. Agents targeting the EGFR axis have shown limited clinical benefits in GBM and the role of EGFRvIII in GBM is poorly understood. To shed light on the role of EGFRvIII and its potential as a therapeutic target, we determined X-ray crystal structures of a monomeric EGFRvIII extracellular region (ECR). The EGFRvIII ECR resembles the unliganded conformation of EGFR, including the orientation of the C-terminal region of domain II. Domain II is mostly disordered, but the ECR structure is compact. We selected a nanobody with preferential binding to EGFRvIII relative to EGFR and structurally defined an epitope on domain IV that is occluded in the unliganded intact EGFR. These findings suggest new avenues for EGFRvIII targeting in GBM.

Keywords: VHH domain; X-ray crystallography; epidermal growth factor receptor; epidermal growth factor receptor variant III; glioblastoma multiforme; nanobody; oncogenic mutation.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • ErbB Receptors* / chemistry
  • ErbB Receptors* / genetics
  • ErbB Receptors* / metabolism
  • Glioblastoma / metabolism
  • Humans
  • Models, Molecular
  • Protein Binding*
  • Protein Domains
  • Single-Domain Antibodies* / chemistry
  • Single-Domain Antibodies* / metabolism

Substances

  • ErbB Receptors
  • epidermal growth factor receptor VIII
  • Single-Domain Antibodies
  • EGFR protein, human