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Pathway analysis of glioblastoma tissue after preoperative treatment with the EGFR tyrosine kinase inhibitor gefitinib--a phase II trial

Hegi, Monika E. and Diserens, Annie-Claire and Bady, Pierre and Kamoshima, Yuta and Kouwenhoven, Mathilde C. M. and Delorenzi, Mauro and Lambiv, Wanyu L. and Hamou, Marie-France and Matter, Matthias S. and Koch, Arend and Heppner, Frank L. and Yonekawa, Yasuhiro and Merlo, Adrian and Frei, Karl and Mariani, Luigi and Hofer, Silvia. (2011) Pathway analysis of glioblastoma tissue after preoperative treatment with the EGFR tyrosine kinase inhibitor gefitinib--a phase II trial. Molecular cancer therapeutics, Vol. 10, H. 6. pp. 1102-1112.

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Official URL: http://edoc.unibas.ch/dok/A6004713

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Abstract

Amplification of the epidermal growth factor receptor (EGFR) gene is one of the most common oncogenic alterations in glioblastoma (45%) making it a prime target for therapy. However, small molecule inhibitors of the EGFR tyrosine kinase showed disappointing efficacy in clinical trials for glioblastoma. Here we aimed at investigating the molecular effects of the tyrosine kinase inhibitor gefitinib on the EGFR signaling pathway in human glioblastoma. Twenty-two patients selected for reoperation of recurrent glioblastoma were treated within a phase II trial for 5 days with 500 mg gefitinib before surgery followed by postoperative gefitinib until recurrence. Resected glioblastoma tissues exhibited high concentrations of gefitinib (median, 4.1 ?g/g), 20 times higher than respective plasma. EGFR-pathway activity was evaluated with phosphorylation-specific assays. The EGFR was efficiently dephosphorylated in treated patients as compared to a control cohort of 12 patients. However, no significant effect on 12 pathway constituents was detected. In contrast, in vitro treatment of a glioblastoma cell line, BS-153, with endogenous EGFRwt amplification and EGFRvIII expression resulted not only in dephosphorylation of the EGFR, but also of key regulators in the pathway such as AKT. Treating established xenografts of the same cell line as an in vivo model showed dephosphorylation of the EGFR without affecting downstream signal transductors, similar to the human glioblastoma. Taken together, gefitinib reaches high concentrations in the tumor tissue and efficiently dephosphorylates its target. However, regulation of downstream signal transducers in the EGFR pathway seems to be dominated by regulatory circuits independent of EGFR phosphorylation.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Brain Tumor Biology (Mariani)
UniBasel Contributors:Mariani, Luigi
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Association for Cancer Research
ISSN:1535-7163
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:31 Jan 2014 09:49
Deposited On:31 Jan 2014 09:49

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