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Epidermal growth factor receptor as a molecular determinant of glioblastoma response to dopamine receptor D2
Yuyu He1, Jie Li1, Tomoyuki Koga1
1Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA.
Background:
There are ongoing clinical trials exploring the efficacy of dopamine receptor D2 (DRD2) inhibition against glioblastomas, the most common primary brain tumor. Here we examine potential molecular determinants of this efficacy.
Methods:
The Cancer Genome Atlas glioblastoma database and other published mRNA profiles were used to analyze the DRD2 and epidermal growth factor receptor (EGFR) expression pattern. In vitro and in vivo responses to DRD2 inhibitors were determined using patient-derived xenograft (PDX) glioblastoma models. Immunohistochemical studies were performed on clinically annotated glioblastoma samples derived from patients treated with ONC201.
Results:
Analysis of clinical glioblastoma specimens derived from independent patient cohorts revealed an inverse correlation between EGFR and DRD2 mRNA expression, with implication that signaling mediated by these proteins shares overlapping functions. In independent panels of PDX glioblastoma lines, high EGFR expression was associated with poor in vitro and in vivo response to DRD2 inhibitors, including haloperidol and ONC201. Moreover, ectopic expression of a constitutively active EGFR, variant (v)III, suppressed glioblastoma sensitivity to ONC201. DRD2 expression positively correlated with expression of rate-limiting enzymes for dopamine synthesis as well as dopamine secretion, suggesting contribution of autocrine DRD2 signaling. Analysis of specimens from patients treated with ONC201 (n = 15) showed an inverse correlation between the intensity of EGFR staining and clinical response. The median overall survival for patients with high and low EGFR staining was 162 and 373 days, respectively (0.037).
Conclusions:
High EGFR expression is a determinant of poor glioblastoma response to DRD2. This finding should inform future clinical trial designs.
Insights
High EGFR expression predicts poor glioblastoma response to dopamine receptor D2 (DRD2) inhibitors. This finding is crucial for optimizing future clinical trials targeting brain tumors.
Area of Science:
- Oncology
- Neuro-oncology
- Molecular Biology
Background:
- Glioblastomas are aggressive primary brain tumors.
- Dopamine receptor D2 (DRD2) inhibition is being investigated as a therapeutic strategy.
- Understanding molecular determinants of treatment efficacy is critical.
Purpose of the Study:
- To investigate the role of epidermal growth factor receptor (EGFR) in glioblastoma response to DRD2 inhibition.
- To identify molecular predictors of treatment outcome for DRD2-targeted therapies.
Main Methods:
- Analysis of The Cancer Genome Atlas and mRNA profiles for DRD2 and EGFR expression.
- Assessment of patient-derived xenograft (PDX) glioblastoma models for in vitro and in vivo response to DRD2 inhibitors.
- Immunohistochemical analysis of glioblastoma samples from patients treated with ONC201.
Main Results:
- An inverse correlation was observed between EGFR and DRD2 mRNA expression in glioblastoma specimens.
- High EGFR expression in PDX models correlated with poor response to DRD2 inhibitors (haloperidol, ONC201).
- EGFR variant III expression reduced glioblastoma sensitivity to ONC201, and high EGFR staining predicted poorer clinical response and survival in patients treated with ONC201.
Conclusions:
- Elevated EGFR expression is a key determinant of poor response to DRD2-targeted therapies in glioblastoma.
- These findings have significant implications for the design of future clinical trials involving DRD2 inhibitors.
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