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dc.contributor.authorJun, Hyun Jungen_US
dc.contributor.authorAcquaviva, Jaimeen_US
dc.contributor.authorChi, Dorcasen_US
dc.contributor.authorLessard, Julieen_US
dc.contributor.authorZhu, Haihaoen_US
dc.contributor.authorWoolfenden, Steveen_US
dc.contributor.authorBronson, Roderick T.en_US
dc.contributor.authorPfannl, Rolfen_US
dc.contributor.authorWhite, Foresten_US
dc.contributor.authorHousman, David E.en_US
dc.contributor.authorIyer, Lakshmananen_US
dc.contributor.authorWhittaker, Charles A.en_US
dc.contributor.authorBoskovitz, Abrahamen_US
dc.contributor.authorRaval, Amien_US
dc.contributor.authorCharest, Alainen_US
dc.date.accessioned2014-03-10T16:17:19Z
dc.date.issued2013en_US
dc.identifier.citationJun, H. J., J. Acquaviva, D. Chi, J. Lessard, H. Zhu, S. Woolfenden, R. T. Bronson, et al. 2013. “Acquired MET Expression Confers Resistance to EGFR Inhibition In a Mouse Model of Glioblastoma Multiforme.” Oncogene 31 (25): 3039-3050. doi:10.1038/onc.2011.474. http://dx.doi.org/10.1038/onc.2011.474.en
dc.identifier.issn0950-9232en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11877079
dc.description.abstractGlioblastoma Multiforme (GBM) is an aggressive brain tumor for which there is no cure. Overexpression of wild-type 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 a key 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.en
dc.language.isoen_USen
dc.relation.isversionofdoi:10.1038/onc.2011.474en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774279/pdf/en
dash.licenseLAAen_US
dc.subjectGlioblastomaen
dc.subjectgenetically engineered mouse modelen
dc.subjectEGFRen
dc.subjectPTENen
dc.subjectc-METen
dc.titleAcquired MET Expression Confers Resistance to EGFR Inhibition In a Mouse Model of Glioblastoma Multiformeen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalOncogeneen
dash.depositing.authorBronson, Roderick T.en_US
dc.date.available2014-03-10T16:17:19Z
dc.identifier.doi10.1038/onc.2011.474*
dash.authorsorderedfalse
dash.contributor.affiliatedBronson, Roderick


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