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.
Copyright © 2018 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Aged
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Animals
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Antibodies, Monoclonal / pharmacology*
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Antineoplastic Agents, Immunological / pharmacology*
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Brain Neoplasms / diagnostic imaging
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Brain Neoplasms / genetics*
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Brain Neoplasms / metabolism
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Child
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Child, Preschool
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / genetics*
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ErbB Receptors / immunology
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ErbB Receptors / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Genetic Predisposition to Disease
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Glioblastoma / diagnostic imaging
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Glioblastoma / genetics*
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Glioblastoma / metabolism
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Humans
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Image Interpretation, Computer-Assisted
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Infant
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Infant, Newborn
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Maschinelles Lernen
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Magnetic Resonance Imaging*
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Male
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Matrix Metalloproteinase 1 / metabolism
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Mice, Nude
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Middle Aged
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Mutation, Missense*
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Neoplasm Invasiveness
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Phenotype
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Phosphorylation
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Predictive Value of Tests
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Protein Domains
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Retrospective Studies
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Signal Transduction / drug effects
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Xenograft Model Antitumor Assays
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Young Adult
Substances
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Antibodies, Monoclonal
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Antineoplastic Agents, Immunological
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epidermal growth factor receptor VIII
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monoclonal antibody 806
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EGFR protein, human
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ErbB Receptors
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Extracellular Signal-Regulated MAP Kinases
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MMP1 protein, human
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Matrix Metalloproteinase 1