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

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 (EGFR A289D/T/V ). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFR A289D/T/V mutants, corroborated in mice bearing intracranial tumors expressing EGFR A289V and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFR A289V 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 EGFR A289V mutation in glioblastoma, postulating EGFR A289V as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies.