Abstract | BACKGROUND: METHODS: Functional effects of erlotinib, gefitinib, and cetuximab on BS153 proliferation, migration, and EGFR-dependent signal transduction were systematically compared in vitro. The tumor-initiating capacity of parental and treatment-resistant BS153 was studied in Naval Medical Research Institute/Foxn1(nu) mice. Potential mediators of resistance were knocked down using small interfering (si) RNA. RESULTS:
Erlotinib and gefitinib inhibited proliferation and migration of BS153 in a dose-dependent manner, whereas cetuximab had no effect. BS153 developed resistance to erlotinib (BS153(resE)) but not to gefitinib. Resistance was associated with strong upregulation of EGFRvIII and subsequent activation of the phosphatidylinositol-3-OH kinase (PI3K) pathway in BS153(resE) and an increased expression of the regulatory 110-kDa delta subunit of PI3K (p110δ). Knockdown of EGFRvIII in BS153(resE) largely restored sensitivity to erlotinib. Targeting PI3K pharmacologically caused a significant decrease in cell viability, and specifically targeting p110δ by siRNA partially restored erlotinib sensitivity in BS153(resE). In vivo, BS153 formed highly invasive tumors with an unusual growth pattern, displaying numerous satellites distant from the initial injection site. Erlotinib resistance led to delayed onset of tumor growth as well as prolonged overall survival of mice without changing tumor morphology. CONCLUSIONS:
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Authors | Alexander Schulte, Katrin Liffers, Annegret Kathagen, Sabine Riethdorf, Svenja Zapf, Adrian Merlo, Katharina Kolbe, Manfred Westphal, Katrin Lamszus |
Journal | Neuro-oncology
(Neuro Oncol)
Vol. 15
Issue 10
Pg. 1289-301
(Oct 2013)
ISSN: 1523-5866 [Electronic] England |
PMID | 23877316
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Forkhead Transcription Factors
- Protein Kinase Inhibitors
- Quinazolines
- Whn protein
- epidermal growth factor receptor VIII
- Erlotinib Hydrochloride
- Phosphatidylinositol 3-Kinases
- EGFR protein, human
- ErbB Receptors
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Topics |
- Animals
- Apoptosis
- Blotting, Western
- Brain Neoplasms
(drug therapy, metabolism, pathology)
- Cell Survival
- Drug Resistance, Neoplasm
- ErbB Receptors
(genetics, metabolism)
- Erlotinib Hydrochloride
- Flow Cytometry
- Fluorescent Antibody Technique
- Forkhead Transcription Factors
(physiology)
- Gene Amplification
- Glioblastoma
(drug therapy, metabolism, pathology)
- Humans
- Immunoenzyme Techniques
- In Situ Hybridization, Fluorescence
- Mice
- Mice, Nude
- Phosphatidylinositol 3-Kinases
(metabolism)
- Protein Kinase Inhibitors
(pharmacology)
- Quinazolines
(pharmacology)
- Signal Transduction
- Tumor Cells, Cultured
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