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

Zev A. Binder, Amy Haseley Thorne, Spyridon Bakas, E. Paul Wileyto, Michel Bilello, Hamed Akbari, Saima Rathore, Sung Min Ha, Logan Zhang, Cole J. Ferguson, Sonika Dahiya, Wenya Linda Bi, David A. Reardon, Ahmed Idbaih, Joerg Felsberg, Bettina Hentschel, Michael Weller, Stephen J. Bagley, Jennifer J.D. Morrissette, MacLean P. NasrallahJianhui Ma, Ciro Zanca, Andrew M. Scott, Laura Orellana, Christos Davatzikos, Frank B. Furnari, Donald M. O'Rourke

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

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.

Original languageEnglish
Pages (from-to)163-177.e7
JournalCancer Cell
Volume34
Issue number1
DOIs
StatePublished - Jul 9 2018

Keywords

  • A289D/T/V
  • EGFR
  • EGFR oncogenes
  • EGFR targeted therapy
  • GBM
  • glioblastoma
  • glioma
  • radiogenomics
  • radiomics
  • survival

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