title: Pathway analysis of glioblastoma tissue after preoperative treatment with the EGFR tyrosine kinase inhibitor gefitinib--a phase II trial.
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 μg/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.
authors.affiliation: Laboratory of Brain Tumor Biology and Genetics, Department of Neurosurgery, LausanneUniversity Hospital and University of Lausanne, Lausanne, Switzerland. Monika.Hegi@chuv.ch
authors.forename: Monika E
authors.initials: ME
authors.lastname: Hegi
authors.forename: Annie-Claire
authors.initials: AC
authors.lastname: Diserens
authors.forename: Pierre
authors.initials: P
authors.lastname: Bady
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kamoshima
authors.forename: Mathilde C M
authors.initials: MC
authors.lastname: Kouwenhoven
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.forename: Wanyu L
authors.initials: WL
authors.lastname: Lambiv
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Hamou
authors.forename: Matthias S
authors.initials: MS
authors.lastname: Matter
authors.forename: Arend
authors.initials: A
authors.lastname: Koch
authors.forename: Frank L
authors.initials: FL
authors.lastname: Heppner
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yonekawa
authors.forename: Adrian
authors.initials: A
authors.lastname: Merlo
authors.forename: Karl
authors.initials: K
authors.lastname: Frei
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.forename: Silvia
authors.initials: S
authors.lastname: Hofer
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib