Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme
Autor: | Steve Woolfenden, Lakshmanan K. Iyer, Jaime Acquaviva, Abraham Boskovitz, Alain Charest, David E. Housman, Haihao Zhu, Forest M. White, Dorcas Chi, Julie Lessard, Charles A. Whittaker, Hyun Jung Jun, Rolf Pfannl, Roderick T. Bronson, Ami P. Raval |
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Přispěvatelé: | Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, White, Forest M., Housman, David E., Whittaker, Charles A., Charest, Alain |
Rok vydání: | 2011 |
Předmět: |
PTEN
Cancer Research Cell cycle checkpoint C-Met EGFR Mice Transgenic Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Genetics medicine Animals Humans Genes Tumor Suppressor Epidermal growth factor receptor Kinase activity Molecular Biology c-MET 030304 developmental biology 0303 health sciences biology Cancer Proto-Oncogene Proteins c-met medicine.disease Molecular biology genetically engineered mouse model 3. Good health ErbB Receptors Disease Models Animal chemistry 030220 oncology & carcinogenesis biology.protein Cancer research Cyclin-dependent kinase 8 Glioblastoma Tyrosine kinase |
Zdroj: | PMC Oncogene |
ISSN: | 1476-5594 0950-9232 |
Popis: | Glioblastoma multiforme (GBM) is an aggressive brain tumor for which there is no cure. Overexpression of wild-type epidermal growth factor receptor (EGFR) and loss of the tumor suppressor genes Ink4a/Arf and PTEN are salient features of this deadly cancer. Surprisingly, targeted inhibition of EGFR has been clinically disappointing, demonstrating an innate ability for GBM to develop resistance. Efforts at modeling GBM in mice using wild-type EGFR have proven unsuccessful to date, hampering endeavors at understanding molecular mechanisms of therapeutic resistance. Here, we describe a unique genetically engineered mouse model of EGFR-driven gliomagenesis that uses a somatic conditional overexpression and chronic activation of wild-type EGFR in cooperation with deletions in the Ink4a/Arf and PTEN genes in adult brains. Using this model, we establish that chronic activation of wild-type EGFR with a ligand is necessary for generating tumors with histopathological and molecular characteristics of GBMs. We show that these GBMs are resistant to EGFR kinase inhibition and we define this resistance molecularly. Inhibition of EGFR kinase activity using tyrosine kinase inhibitors in GBM tumor cells generates a cytostatic response characterized by a cell cycle arrest, which is accompanied by a substantial change in global gene expression levels. We demonstrate that an important component of this pattern is the transcriptional activation of the MET receptor tyrosine kinase and that pharmacological inhibition of MET overcomes the resistance to EGFR inhibition in these cells. These findings provide important new insights into mechanisms of resistance to EGFR inhibition and suggest that inhibition of multiple targets will be necessary to provide therapeutic benefit for GBM patients. National Institutes of Health (U.S.) (Grant NCI U01 CA141556) American Cancer Society (Research Scholar Award 1117409) National Institutes of Health (U.S.) (Grant U54 CA119349) |
Databáze: | OpenAIRE |
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