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dc.contributor.authorCooper, J
dc.contributor.authorXu, Q
dc.contributor.authorZhou, L
dc.contributor.authorPavlovic, M
dc.contributor.authorOjeda, V
dc.contributor.authorMoulick, K
dc.contributor.authorde Stanchina, E
dc.contributor.authorPoirier, JT
dc.contributor.authorZauderer, M
dc.contributor.authorRudin, CM
dc.contributor.authorKarajannis, MA
dc.contributor.authorHanemann, Clemens Oliver
dc.contributor.authorGiancotti, FG
dc.date.accessioned2017-06-22T13:06:04Z
dc.date.available2017-06-22T13:06:04Z
dc.date.issued2017-05-03
dc.identifier.issn1535-7163
dc.identifier.issn1538-8514
dc.identifier.urihttp://hdl.handle.net/10026.1/9516
dc.description.abstract

<jats:title>Abstract</jats:title> <jats:p>Inactivation of NF2/Merlin causes the autosomal-dominant cancer predisposition syndrome familial neurofibromatosis type 2 (NF2) and contributes to the development of malignant pleural mesothelioma (MPM). To develop a targeted therapy for NF2-mutant tumors, we have exploited the recent realization that Merlin loss drives tumorigenesis by activating the E3 ubiquitin ligase CRL4DCAF1, thereby inhibiting the Hippo pathway component Lats. Here, we show that MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, suppresses CRL4DCAF1 and attenuates activation of YAP in NF2-mutant tumor cells. In addition, MLN4924 sensitizes MPM to traditional chemotherapy, presumably as a result of collateral inhibition of cullin-RING ubiquitin ligases (CRL) involved in DNA repair. However, even in combination with chemotherapy, MLN4924 does not exhibit significant preclinical activity. Further analysis revealed that depletion of DCAF1 or treatment with MLN4924 does not affect mTOR hyperactivation in NF2-mutant tumor cells, suggesting that loss of Merlin activates mTOR independently of CRL4DCAF1. Intriguingly, combining MLN4924 with the mTOR/PI3K inhibitor GDC-0980 suppresses the growth of NF2-mutant tumor cells in vitro as well as in mouse and patient-derived xenografts. These results provide preclinical rationale for the use of NAE inhibitors in combination with mTOR/PI3K inhibitors in NF2-mutant tumors.</jats:p>

dc.format.extentmolcanther.0821.2016-molcanther.0821.2016
dc.format.mediumPrint-Electronic
dc.languageen
dc.language.isoen
dc.publisherAmerican Association for Cancer Research (AACR)
dc.subjectAnimals
dc.subjectCarcinogenesis
dc.subjectCell Line, Tumor
dc.subjectCell Proliferation
dc.subjectCyclopentanes
dc.subjectHumans
dc.subjectLung Neoplasms
dc.subjectMesothelioma
dc.subjectMesothelioma, Malignant
dc.subjectMice
dc.subjectMutation
dc.subjectNeurofibromin 2
dc.subjectOncogenes
dc.subjectPhosphatidylinositol 3-Kinases
dc.subjectPleural Neoplasms
dc.subjectPyrimidines
dc.subjectSignal Transduction
dc.subjectTOR Serine-Threonine Kinases
dc.subjectUbiquitin-Activating Enzymes
dc.titleCombined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis
dc.typejournal-article
dc.typeJournal Article
plymouth.author-urlhttps://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000406929200022&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=11bb513d99f797142bcfeffcc58ea008
plymouth.issue8
plymouth.volume16
plymouth.publication-statusPublished online
plymouth.journalMolecular Cancer Therapeutics
dc.identifier.doi10.1158/1535-7163.MCT-16-0821
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/Research Groups
plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)
plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)/CBR
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
plymouth.organisational-group/Plymouth/Users by role/Researchers in ResearchFish submission
dc.publisher.placeUnited States
dcterms.dateAccepted2017-04-20
dc.rights.embargodate2018-5-3
dc.identifier.eissn1538-8514
dc.rights.embargoperiod12 months
rioxxterms.versionofrecord10.1158/1535-7163.MCT-16-0821
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2017-05-03
rioxxterms.typeJournal Article/Review


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