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EGFR inhibition using gefitinib is not active in neuroblastoma cell lines
Jochen Rössler1, Eva Odenthal, Birgit Geoerger
1Department of Pediatrics and Adolescent Medicine, University Hospital of Freiburg, 79106 Freiburg, Germany. jochen.roessler@uniklinik-freiburg.de
Background:
Inhibition of the epidermal growth factor receptor (EGFR), using a tyrosine kinase inhibitor such as gefitinib, was suggested to be a new treatment approach for neuroblastoma.
Material And Methods:
EGFR expression and gene mutation were studied by reversetranscriptase-polxmerase chain reacting, fluorescence-activated cell sorting and gene sequencing in six neuroblastoma cell lines. In vitro cytotoxicity of gefitinib 0.1-10 microM alone or in combination with topotecan, vincristine and 9-cis retinoic acid (9cisRA) was determined by MTT proliferation assay.
Results:
EGFR overexpression and gene mutations were absent in all cell lines tested. Inhibition of cell viability of 62-85% was found at 10 microM gefitinib, concentrations that, however, can clinically not be reached. In addition, gefitinib increased inhibitory effects of topotecan, vincristine and RA by 10-15% .
Conclusion:
Our in vitro data do not support the use of gefitinib as monotherapy in neuroblastoma and its chemosensitizing effects appear minor.
Insights
Gefitinib does not show promise as a standalone neuroblastoma treatment. While it slightly enhanced chemotherapy effectiveness in vitro, its high concentrations are not clinically achievable, limiting its therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal Growth Factor Receptor (EGFR) inhibition with tyrosine kinase inhibitors like gefitinib was proposed as a novel neuroblastoma treatment.
- EGFR signaling is implicated in various cancers, prompting investigation into its role in neuroblastoma.
Purpose of the Study:
- To evaluate the efficacy of gefitinib as a monotherapy for neuroblastoma.
- To assess the potential of gefitinib in combination with standard chemotherapeutic agents for neuroblastoma treatment.
Main Methods:
- EGFR expression and mutations were analyzed in six neuroblastoma cell lines using RT-PCR, FACS, and gene sequencing.
- In vitro cytotoxicity of gefitinib, alone and combined with topotecan, vincristine, and 9-cis retinoic acid (9cisRA), was determined via MTT assay.
Main Results:
- EGFR overexpression and mutations were not detected in any of the tested neuroblastoma cell lines.
- Gefitinib demonstrated significant inhibition of cell viability (62-85%) at 10 microM, but these concentrations are clinically unattainable.
- Gefitinib showed a modest enhancement (10-15%) of the inhibitory effects of topotecan, vincristine, and 9cisRA.
Conclusions:
- The in vitro findings do not support the use of gefitinib as a monotherapy for neuroblastoma.
- The observed chemosensitizing effects of gefitinib in combination therapies were minor, suggesting limited clinical utility.
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