期刊
CANCER CELL
卷 34, 期 1, 页码 163-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2018.06.006
关键词
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资金
- Templeton Family Initiative in Neuro-Oncology
- NCI [2T32CA009523-29A1, U24CA189523]
- Ligue National Contre le Cancer
- Lawski Fund for Biomedical Research
- NINDS [R01NS042645]
- NCATS [UL1TR001878]
- ITMAT of the University of Pennsylvania
- NBTS: Defeat GBM Research Collaborative, NIH [RO1NS080939]
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.
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