Glioblastoma-Derived Epidermal Growth Factor Receptor Carboxyl-Terminal Deletion Mutants Are Transforming and Are Sensitive to EGFR-Directed Therapies
| Autor: | Matthew Meyerson, Derek Y. Chiang, Amit Dutt, Ying S. Chao, Sandra Pastorino, William D. Johnson, Robert C. Onofrio, Roel G.W. Verhaak, Jihyun Kwon, Hideo Watanabe, Yuki Yuza, Jeonghee Cho, Santosh Kesari, Andrew D. Cherniack, Xiaoyin Xu, Qing Treitler Zeng, Scott R. VandenBerg |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Cetuximab Antineoplastic Agents Kaplan-Meier Estimate Mice SCID Biology Antibodies Monoclonal Humanized medicine.disease_cause Article Cell Line Erlotinib Hydrochloride Mice Exon Cell Line Tumor medicine Animals Humans Epidermal growth factor receptor Phosphorylation Protein Kinase Inhibitors neoplasms Cell Proliferation EGFR inhibitors Mutation Brain Neoplasms Antibodies Monoclonal Exons Xenograft Model Antitumor Assays Molecular biology Tumor Burden ErbB Receptors Cell Transformation Neoplastic Oncology NIH 3T3 Cells Quinazolines biology.protein Erlotinib CTD Glioblastoma Gene Deletion medicine.drug |
| Zdroj: | Cancer Research. 71:7587-7596 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Genomic alterations of the epidermal growth factor receptor (EGFR) gene play a crucial role in pathogenesis of glioblastoma multiforme (GBM). By systematic analysis of GBM genomic data, we have identified and characterized a novel exon 27 deletion mutation occurring within the EGFR carboxyl-terminus domain (CTD), in addition to identifying additional examples of previously reported deletion mutations in this region. We show that the GBM-derived EGFR CTD deletion mutants are able to induce cellular transformation in vitro and in vivo in the absence of ligand and receptor autophosphorylation. Treatment with the EGFR-targeted monoclonal antibody, cetuximab, or the small molecule EGFR inhibitor, erlotinib, effectively impaired tumorigenicity of oncogenic EGFR CTD deletion mutants. Cetuximab in particular prolonged the survival of intracranially xenografted mice with oncogenic EGFR CTD deletion mutants, compared with untreated control mice. Therefore, we propose that erlotinib and, especially, cetuximab treatment may be a promising therapeutic strategy in GBM patients harboring EGFR CTD deletion mutants. Cancer Res; 71(24); 7587–96. ©2011 AACR. |
| Databáze: | OpenAIRE |
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