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Updated: May 5, 2026
Isolation and Flow Cytometric Analysis of Glioma-infiltrating Peripheral Blood Mononuclear Cells
Published on: November 28, 2015
Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular
Jeffrey C Lee1, Igor Vivanco, Rameen Beroukhim
1Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute Harvard Medical School, Boston, Massachusetts, United States of America.
Background:
Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy.
Methods And Findings:
Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors.
Conclusions:
Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.
Insights
Novel EGFR mutations in the extracellular domain were found in glioblastomas, driving cancer growth. These mutations suggest a new way to activate EGFR and may identify patients for EGFR inhibitor therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Protein tyrosine kinases regulate cellular homeostasis; mutations can cause cancer.
- Epidermal growth factor receptor (EGFR) kinase inhibitors show promise in glioblastoma treatment.
- Missense mutations in the EGFR kinase domain are linked to therapeutic responses.
Purpose of the Study:
- To investigate the role of EGFR mutations in glioblastoma.
- To identify novel EGFR mutations and their functional consequences.
- To explore potential therapeutic targets for glioblastoma.
Main Methods:
- Sequencing of the complete EGFR coding sequence in glioma samples and cell lines.
- Analysis of EGFR gene dosage and mutation frequency.
- Functional studies using NIH-3T3 cells to assess transformation and tumorigenicity.
Main Results:
- Novel missense mutations in the extracellular domain of EGFR identified in 13.6% of glioblastomas.
- These mutations correlated with increased EGFR gene dosage.
- EGFR mutants conferred anchorage-independent growth and tumorigenicity, and cells were sensitive to EGFR kinase inhibitors.
Conclusions:
- Extracellular missense mutations represent a novel mechanism for oncogenic EGFR activation.
- These findings may aid in identifying glioblastoma patients who can benefit from EGFR kinase inhibitors.
- The study highlights the importance of investigating extracellular domains for cancer-driving mutations.
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