Binder ZA, Thorne AH, Bakas S, Wileyto EP, Bilello M, Akbari H, Rathore S, Ha SM, Zhang L, Ferguson CJ, Dahiya S, Bi WL, Reardon DA, Idbaih A, Felsberg J, Hentschel B, Weller M, Bagley SJ, Morrissette JJD, Nasrallah MP, Ma J, Zanca C, Scott AM, Orellana L, Davatzikos C, Furnari FB, O'Rourke DM
Cancer Cell 34 (1) 163-177.e7 [2018-07-09; online 2018-07-11]
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 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.