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Published on: March 28, 2021
A novel small molecule that selectively inhibits glioblastoma cells expressing EGFRvIII
Dimitri G Trembath1, Anita Lal, David J Kroll
1Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. dtremba1@jhmi.edu
Background:
Mutations of the epidermal growth factor receptor (EGFR) are a possible molecular target for cancer therapy. EGFR is frequently amplified in glioblastomas and 30 to 40% of glioblastomas also express the deletion mutation EGFRvIII. This frequent oncogenic mutation provides an opportunity for identifying new anti-glioblastoma therapies. In this study, we sought small molecule inhibitors specific for cancer cells expressing EGFRvIII, using isogenic parental cells without EGFRvIII as a control.
Results:
A screen of the NCI small molecule diversity set identified one compound, NSC-154829, which consistently inhibited growth of different human glioblastoma cells expressing EGFRvIII, but permitted normal growth of matched control cells. NSC-154829 had no previously established medicinal use, but has a purine-like structural component. Further experiments showed this compound increased apoptosis in cells with EGFRvIII, and moderately affected the expression of p21, independent of any changes in p53 levels or in Akt phosphorylation.
Conclusion:
These initial results suggest that NSC-154829 or a closely related structure might be further investigated for its potential as an anti-glioblastoma drug, although its precise molecular mechanism is still undefined.
Insights
A novel compound, NSC-154829, effectively inhibits growth in glioblastoma cells with the epidermal growth factor receptor (EGFR) deletion mutation (EGFRvIII). This targeted approach offers potential for new glioblastoma therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Epidermal growth factor receptor (EGFR) mutations are key targets in cancer therapy.
- EGFR amplification and the specific EGFRvIII mutation are prevalent in glioblastomas.
- EGFRvIII presents a therapeutic opportunity for novel anti-glioblastoma strategies.
Purpose of the Study:
- To identify small molecule inhibitors specifically targeting cancer cells with EGFRvIII.
- To utilize isogenic parental cells lacking EGFRvIII as controls for specificity screening.
Main Methods:
- Screening of the NCI small molecule diversity set.
- Assessing compound efficacy on glioblastoma cell lines with and without EGFRvIII.
- Evaluating effects on apoptosis, p21 expression, p53 levels, and Akt phosphorylation.
Main Results:
- NSC-154829 selectively inhibited growth of EGFRvIII-expressing glioblastoma cells.
- The compound induced apoptosis in EGFRvIII-positive cells.
- NSC-154829 moderately affected p21 expression independently of p53 or Akt pathways.
Conclusions:
- NSC-154829 shows promise as a potential anti-glioblastoma therapeutic agent.
- Further investigation of NSC-154829 or related structures is warranted.
- The precise molecular mechanism of NSC-154829 requires further elucidation.
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