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Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib
Daphne A Haas-Kogan1, Michael D Prados, Tarik Tihan
1Department of Neurosurgery, Brain Tumor Research Center, University of California-San Francisco, 1600 Divisadero Street, Suite H1031, San Francisco, CA 94143, USA. hkogan@radonc17.ucsf.edu
Background:
The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib (also known as Tarceva or OSI-774) has shown promising response rates in malignant gliomas. We investigated the association between expression of EGFR and downstream signaling components and the response of malignant gliomas to erlotinib in a phase I trial of erlotinib administered either alone or with the alkylating agent temozolomide.
Methods:
Expression of EGFR and ligand-independent EGFRvIII mutant proteins and of phosphorylated protein kinase B (PKB)/Akt in specimens from glioma patients were assessed by immunohistochemistry. EGFR gene amplification was evaluated by fluorescence in situ hybridization. Mutations in PTEN and EGFR were assessed by polymerase chain reaction amplification and sequencing. Response was evaluated by sequential magnetic resonance imaging every 2 months. The Cochran-Mantel-Haenzel test was used to assess associations between biomarker status and response. All statistical tests were two-sided.
Results:
Of 41 glioma patients, eight responded to treatment. Response to erlotinib was associated with EGFR expression (P = .07) and EGFR amplification (P = .08). These associations were stronger and statistically significant among the 29 patients initially diagnosed with glioblastoma multiforme (P = .03 and P = .02, respectively). Among six responders with sufficient tumor tissue, none had EGFRvIII mutations. None of the 22 tumors with high levels of phosphorylated PKB/Akt responded to erlotinib treatment, whereas eight of the 18 tumors with low levels of phosphorylated PKB/Akt responded to erlotinib treatment (P < .001). The level of phosphorylated PKB/Akt was also associated with time to progression (P < .001).
Conclusions:
Among glioma patients, those with glioblastoma multiforme tumors who have high levels of EGFR expression and low levels of phosphorylated PKB/Akt had better response to erlotinib treatment than those with low levels of EGFR expression and high levels of phosphorylated PKB/Akt.
Insights
Erlotinib shows promise for malignant gliomas. High epidermal growth factor receptor (EGFR) expression and low phosphorylated protein kinase B/Akt levels predict better erlotinib response in glioblastoma multiforme patients.
Area of Science:
- Oncology
- Molecular Biology
- Clinical Trials
Background:
- Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, demonstrates potential in treating malignant gliomas.
- Investigating biomarkers for erlotinib efficacy is crucial for optimizing treatment strategies.
Purpose of the Study:
- To assess the association between EGFR expression, downstream signaling components, and malignant glioma response to erlotinib.
- To evaluate erlotinib's efficacy alone or combined with temozolomide in a Phase I clinical trial.
Main Methods:
- Immunohistochemistry used to assess EGFR, EGFRvIII mutant proteins, and phosphorylated protein kinase B (PKB)/Akt expression.
- EGFR gene amplification analyzed via fluorescence in situ hybridization; EGFR and PTEN mutations assessed by PCR and sequencing.
- Tumor response evaluated using sequential magnetic resonance imaging; Cochran-Mantel-Haenzel test applied for biomarker association analysis.
Main Results:
- Erlotinib response correlated with EGFR expression and amplification, particularly in glioblastoma multiforme patients.
- No responders exhibited EGFRvIII mutations; high phosphorylated PKB/Akt levels were associated with non-response (P < .001).
- Low phosphorylated PKB/Akt levels predicted favorable response and improved time to progression (P < .001).
Conclusions:
- High EGFR expression and low phosphorylated PKB/Akt levels are predictive biomarkers for erlotinib response in glioblastoma multiforme.
- These findings suggest a targeted approach for erlotinib therapy in specific glioma patient subgroups.
- Further research can refine patient selection for improved outcomes in malignant glioma treatment.
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