Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01.

Lassman AB, Rossi MR, Raizer JJ, Razier JR, Abrey LE, Lieberman FS, Grefe CN, Lamborn K, Pao W, Shih AH, Kuhn JG, Wilson R, Nowak NJ, Cowell JK, DeAngelis LM, Wen P, Gilbert MR, Chang S, Yung WA, Prados M, Holland EC
Clin Cancer Res. 2005 11 (21): 7841-50

PMID: 16278407 · DOI:10.1158/1078-0432.CCR-05-0421

PURPOSE - We investigated the molecular effect of the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib in vivo on all available tumors from patients treated on North American Brain Tumor Consortium trials 01-03 and 00-01 for recurrent or progressive malignant glioma.

EXPERIMENTAL DESIGN - EGFR expression and signaling during treatment with erlotinib or gefitinib were analyzed by Western blot and compared with pre-erlotinib/gefitinib-exposed tissue or unexposed controls. Tumors were also analyzed for EGFR mutations and for other genomic abnormalities by array-based comparative genomic hybridization. Clinical data were used to associate molecular features with tumor sensitivity to erlotinib or gefitinib.

RESULTS - Erlotinib and gefitinib did not markedly affect EGFR activity in vivo. No lung signature mutations of EGFR exons 18 to 21 were observed. There was no clear association between erlotinib/gefitinib sensitivity and deletion or amplification events on array-based comparative genomic hybridization analysis, although novel genomic changes were identified.

CONCLUSIONS - As erlotinib and gefitinib were generally ineffective at markedly inhibiting EGFR phosphorylation in these tumors, other assays may be needed to detect molecular effects. Additionally, the mechanism of erlotinib/gefitinib sensitivity likely differs between brain and lung tumors. Finally, novel genomic changes, including deletions of chromosomes 6, 21, and 22, represent new targets for further research.

MeSH Terms (23)

Antineoplastic Agents Blotting, Western Brain Neoplasms Clinical Trials as Topic Cluster Analysis Disease Progression ErbB Receptors Erlotinib Hydrochloride Exons Gefitinib Gene Deletion Gene Expression Regulation, Neoplastic Genome Glioma Humans Lung Neoplasms Models, Biological Mutation Nucleic Acid Hybridization Protein Kinase Inhibitors Quinazolines Sequence Analysis, DNA Time Factors

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