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dc.contributor.authorJun, Hyun Jung
dc.contributor.authorAcquaviva, Jaime
dc.contributor.authorChi, D.
dc.contributor.authorLessard, Julie
dc.contributor.authorZhu, H.
dc.contributor.authorWoolfenden, S.
dc.contributor.authorBronson, Roderick T.
dc.contributor.authorPfannl, R.
dc.contributor.authorIyer, L.
dc.contributor.authorBoskovitz, Abraham
dc.contributor.authorRaval, A.
dc.contributor.authorWhite, Forest M.
dc.contributor.authorHousman, David E.
dc.contributor.authorWhittaker, Charles A.
dc.contributor.authorCharest, Alain
dc.date.accessioned2014-01-27T15:35:43Z
dc.date.available2014-01-27T15:35:43Z
dc.date.issued2011-10
dc.date.submitted2011-08
dc.identifier.issn0950-9232
dc.identifier.issn1476-5594
dc.identifier.urihttp://hdl.handle.net/1721.1/84554
dc.description.abstractGlioblastoma 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.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant NCI U01 CA141556)en_US
dc.description.sponsorshipAmerican Cancer Society (Research Scholar Award 1117409)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant U54 CA119349)en_US
dc.language.isoen_US
dc.publisherNature Publishing Groupen_US
dc.relation.isversionofhttp://dx.doi.org/10.1038/onc.2011.474en_US
dc.rightsCreative Commons Attribution-Noncommercial-Share Alike 3.0en_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/en_US
dc.sourcePMCen_US
dc.titleAcquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiformeen_US
dc.typeArticleen_US
dc.identifier.citationJun, H J, J Acquaviva, D Chi, J Lessard, H Zhu, S Woolfenden, R T Bronson, et al. “Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme.” Oncogene 31, no. 25 (October 24, 2011): 3039-3050.en_US
dc.contributor.departmentDavid H. Koch Institute for Integrative Cancer Research at MITen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorWhite, Forest M.en_US
dc.contributor.mitauthorHousman, David E.en_US
dc.contributor.mitauthorWhittaker, Charles A.en_US
dc.contributor.mitauthorCharest, Alainen_US
dc.relation.journalOncogeneen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsJun, H J; Acquaviva, J; Chi, D; Lessard, J; Zhu, H; Woolfenden, S; Bronson, R T; Pfannl, R; White, F; Housman, D E; Iyer, L; Whittaker, C A; Boskovitz, A; Raval, A; Charest, Aen_US
dc.identifier.orcidhttps://orcid.org/0000-0002-1545-1651
dc.identifier.orcidhttps://orcid.org/0000-0001-5016-0756
mit.licenseOPEN_ACCESS_POLICYen_US


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