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Oncogene. 2015 Jan 2;34(1):129-34. doi: 10.1038/onc.2013.534. Epub 2013 Dec 23.

EGFR wild type antagonizes EGFRvIII-mediated activation of Met in glioblastoma.

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  • 1Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 31] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Esophagal Diseases Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 4Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 51] Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA [3] Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 61] Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA [3] VA North Texas Health Care System, Dallas, TX, USA.

Abstract

Epidermal growth factor receptor (EGFR)vIII is the most common EGFR mutant found in glioblastoma (GBM). EGFRvIII does not bind ligand, is highly oncogenic and is usually coexpressed with EGFR wild type (EGFRwt). EGFRvIII activates Met, and Met contributes to EGFRvIII-mediated oncogenicity and resistance to treatment. Here, we report that addition of EGF results in a rapid loss of EGFRvIII-driven Met phosphorylation in glioma cells. Met is associated with EGFRvIII in a physical complex. Addition of EGF results in a dissociation of the EGFRvIII-Met complex with a concomitant loss of Met phosphorylation. Consistent with the abrogation of Met activation, addition of EGF results in the inhibition of EGFRvIII-mediated resistance to chemotherapy. Thus, our study suggests that ligand in the milieu of EGFRvIII-expressing GBM cells is likely to influence the EGFRvIII-Met interaction and resistance to treatment, and highlights a novel antagonistic interaction between EGFRwt and EGFRvIII in glioma cells.

PMID:
24362532
[PubMed - indexed for MEDLINE]
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