Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development

Cancer Cell. 2018 Jul 9;34(1):163-177.e7. doi: 10.1016/j.ccell.2018.06.006.

Abstract

We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFRA289D/T/V). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFRA289D/T/V mutants, corroborated in mice bearing intracranial tumors expressing EGFRA289V and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFRA289V tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFRA289V mutation in glioblastoma, postulating EGFRA289V as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies.

Keywords: A289D/T/V; EGFR; EGFR oncogenes; EGFR targeted therapy; GBM; glioblastoma; glioma; radiogenomics; radiomics; survival.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antineoplastic Agents, Immunological / pharmacology*
  • Brain Neoplasms / diagnostic imaging
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Child
  • Child, Preschool
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics*
  • ErbB Receptors / immunology
  • ErbB Receptors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Genetic Predisposition to Disease
  • Glioblastoma / diagnostic imaging
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism
  • Humans
  • Image Interpretation, Computer-Assisted
  • Infant
  • Infant, Newborn
  • Maschinelles Lernen
  • Magnetic Resonance Imaging*
  • Male
  • Matrix Metalloproteinase 1 / metabolism
  • Mice, Nude
  • Middle Aged
  • Mutation, Missense*
  • Neoplasm Invasiveness
  • Phenotype
  • Phosphorylation
  • Predictive Value of Tests
  • Protein Domains
  • Retrospective Studies
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays
  • Young Adult

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents, Immunological
  • epidermal growth factor receptor VIII
  • monoclonal antibody 806
  • EGFR protein, human
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases
  • MMP1 protein, human
  • Matrix Metalloproteinase 1