title: EGFR wild type antagonizes EGFRvIII-mediated activation of Met in glioblastoma.
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.
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: V T
authors.initials: VT
authors.lastname: Puliyappadamba
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rehman
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: V
authors.initials: V
authors.lastname: Vemireddy
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Saha
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Esophagal Diseases Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: R F
authors.initials: RF
authors.lastname: Souza
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Hatanpaa
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Koduru
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Burma
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Boothman
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.|VA North Texas Health Care System, Dallas, TX, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Habib
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000737:chemistry; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D010641:Phenotype; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D000077204:Temozolomide
chemical_list: C410723:epidermal growth factor receptor VIII; D004815:Epidermal Growth Factor; D003606:Dacarbazine; C512478:EGFR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D000077204:Temozolomide