title: The Role of EGFR-Met Interactions in the Pathogenesis of Glioblastoma and Resistance to Treatment.
abstract: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. It is a devastating and intractable disease with a poor outcome. Aberrant receptor tyrosine kinase signaling is a key driver in gliomagenesis and resistance to treatment. EGFR gene amplification and mutations are an important genetic alteration in GBM resulting in increased expression of EGFR wild type (EGFRwt) as well as mutant oncogenic forms of the EGFR. EGFRvIII is the most common oncogenic mutant in GBM and is usually co-expressed with EGFRwt. EGFRvIII does not bind ligand and is constitutively active. Recent studies have also highlighted a key role for Met in gliomagenesis and the EGFR and Met may act in concert to promote the malignant phenotype. Met is transactivated by EGFRvIII and plays a key role in EGFRvIII-mediated resistance to targeted treatment. HGF, a Met ligand, is highly expressed in GBM. HGF and Met create an important autocrine signaling loop that promotes GBM invasion. In addition, HGF/Met is able to induce EGFR activation, leading to enhanced activation of oncogenic signaling in GBM. In this review, we discuss the evidence for EGFR and Met interaction in GBM and discuss the mechanisms and biological consequences of transactivation between the two kinases. Additionally, we discuss the therapeutic potential of targeting both EGFR and Met signaling for the treatment of GBM.
authors.forename: Gao
authors.initials: G
authors.lastname: Guo
authors.forename: Ram N
authors.initials: RN
authors.lastname: Narayan
authors.forename: Lindsay
authors.initials: L
authors.lastname: Horton
authors.forename: Toral R
authors.initials: TR
authors.lastname: Patel
authors.affiliation: University of Texas Southwestern Medical Center, North Texas VA Healthcare System, Mail Code 151, 4500 South Lancaster Road, Dallas TX 75216;.
authors.forename: Amyn A
authors.initials: AA
authors.lastname: Habib
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C410723:epidermal growth factor receptor VIII; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: EGFR; EGFR mutants; EGFRvIII; GBM; Met; antagonistic. EGFR wild type; glioblastoma; glioma; synergistic; targeted treatment