Please use this identifier to cite or link to this item: http://hdl.handle.net/1893/23252
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dc.contributor.authorYogev, Orlien_UK
dc.contributor.authorBarker, Karenen_UK
dc.contributor.authorSikka, Artien_UK
dc.contributor.authorAlmeida, Gilberto Sen_UK
dc.contributor.authorHallsworth, Alberten_UK
dc.contributor.authorSmith, Laura Men_UK
dc.contributor.authorJamin, Yannen_UK
dc.contributor.authorRuddle, Ruthen_UK
dc.contributor.authorKoers, Alexanderen_UK
dc.contributor.authorWebber, Hannahen_UK
dc.contributor.authorRaynaud, Florence Ien_UK
dc.contributor.authorPopov, Sergeyen_UK
dc.contributor.authorJones, Chrisen_UK
dc.contributor.authorPetrie, Kevinen_UK
dc.contributor.authorRobinson, Simon Pen_UK
dc.contributor.authorKeun, Hector Cen_UK
dc.contributor.authorChesler, Louisen_UK
dc.date.accessioned2016-06-16T00:18:25Z-
dc.date.available2016-06-16T00:18:25Z-
dc.date.issued2016-05-15en_UK
dc.identifier.urihttp://hdl.handle.net/1893/23252-
dc.description.abstractNeuroblastoma is the most common childhood extracranial solid tumor. In high-risk cases, many of which are characterized by amplification ofMYCN, outcome remains poor. Mutations in the p53 (TP53) tumor suppressor are rare at diagnosis, but evidence suggests that p53 function is often impaired in relapsed, treatment-resistant disease. To address the role of p53 loss of function in the development and pathogenesis of high-risk neuroblastoma, we generated a MYCN-driven genetically engineered mouse model in which the tamoxifen-inducible p53ERTAMfusion protein was expressed from a knock-in allele (Th-MYCN/Trp53KI). We observed no significant differences in tumor-free survival between Th-MYCNmice heterozygous forTrp53KI(n= 188) and Th-MYCNmice with wild-type p53 (n= 101). Conversely, the survival of Th-MYCN/Trp53KI/KImice lacking functional p53 (n= 60) was greatly reduced. We found that Th-MYCN/Trp53KI/KItumors were resistant to ionizing radiation (IR), as expected. However, restoration of functional p53ERTAMreinstated sensitivity to IR in only 50% of Th-MYCN/Trp53KI/KItumors, indicating the acquisition of additional resistance mechanisms. Gene expression and metabolic analyses indicated that the principal acquired mechanism of resistance to IR in the absence of functional p53 was metabolic adaptation in response to chronic oxidative stress. Tumors exhibited increased antioxidant metabolites and upregulation of glutathione S-transferase pathway genes, includingGstp1andGstz1, which are associated with poor outcome in human neuroblastoma. Accordingly, glutathione depletion by buthionine sulfoximine together with restoration of p53 activity resensitized tumors to IR. Our findings highlight the complex pathways operating in relapsed neuroblastomas and the need for combination therapies that target the diverse resistance mechanisms at play.en_UK
dc.language.isoenen_UK
dc.publisherAmerican Association for Cancer Researchen_UK
dc.relationYogev O, Barker K, Sikka A, Almeida GS, Hallsworth A, Smith LM, Jamin Y, Ruddle R, Koers A, Webber H, Raynaud FI, Popov S, Jones C, Petrie K, Robinson SP, Keun HC & Chesler L (2016) p53 loss in Myc-driven neuroblastoma leads to metabolic adaptations supporting radioresistance. Cancer Research, 76 (10), pp. 3025-3035. https://doi.org/10.1158/0008-5472.CAN-15-1939en_UK
dc.rightsThe publisher does not allow this work to be made publicly available in this Repository. Please use the Request a Copy feature at the foot of the Repository record to request a copy directly from the author. You can only request a copy if you wish to use this work for your own research or private study.en_UK
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_UK
dc.titlep53 loss in Myc-driven neuroblastoma leads to metabolic adaptations supporting radioresistanceen_UK
dc.typeJournal Articleen_UK
dc.rights.embargodate2999-12-30en_UK
dc.rights.embargoreason[Cancer Res-2016-Yogev-3025-35.pdf] The publisher does not allow this work to be made publicly available in this Repository therefore there is an embargo on the full text of the work.en_UK
dc.identifier.doi10.1158/0008-5472.CAN-15-1939en_UK
dc.identifier.pmid27197232en_UK
dc.citation.jtitleCancer Researchen_UK
dc.citation.issn1538-7445en_UK
dc.citation.issn0008-5472en_UK
dc.citation.volume76en_UK
dc.citation.issue10en_UK
dc.citation.spage3025en_UK
dc.citation.epage3035en_UK
dc.citation.publicationstatusPublisheden_UK
dc.citation.peerreviewedRefereeden_UK
dc.type.statusVoR - Version of Recorden_UK
dc.author.emailkevin.petrie@stir.ac.uken_UK
dc.citation.date29/03/2016en_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationImperial College Londonen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationBiological and Environmental Sciencesen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.contributor.affiliationImperial College Londonen_UK
dc.contributor.affiliationInstitute of Cancer Researchen_UK
dc.identifier.isiWOS:000375841000020en_UK
dc.identifier.scopusid2-s2.0-84971505665en_UK
dc.identifier.wtid574129en_UK
dc.contributor.orcid0000-0002-9805-9152en_UK
dc.date.accepted2016-02-09en_UK
dcterms.dateAccepted2016-02-09en_UK
dc.date.filedepositdate2016-05-31en_UK
rioxxterms.apcnot requireden_UK
rioxxterms.typeJournal Article/Reviewen_UK
rioxxterms.versionVoRen_UK
local.rioxx.authorYogev, Orli|en_UK
local.rioxx.authorBarker, Karen|en_UK
local.rioxx.authorSikka, Arti|en_UK
local.rioxx.authorAlmeida, Gilberto S|en_UK
local.rioxx.authorHallsworth, Albert|en_UK
local.rioxx.authorSmith, Laura M|en_UK
local.rioxx.authorJamin, Yann|en_UK
local.rioxx.authorRuddle, Ruth|en_UK
local.rioxx.authorKoers, Alexander|en_UK
local.rioxx.authorWebber, Hannah|en_UK
local.rioxx.authorRaynaud, Florence I|en_UK
local.rioxx.authorPopov, Sergey|en_UK
local.rioxx.authorJones, Chris|en_UK
local.rioxx.authorPetrie, Kevin|0000-0002-9805-9152en_UK
local.rioxx.authorRobinson, Simon P|en_UK
local.rioxx.authorKeun, Hector C|en_UK
local.rioxx.authorChesler, Louis|en_UK
local.rioxx.projectInternal Project|University of Stirling|https://isni.org/isni/0000000122484331en_UK
local.rioxx.freetoreaddate2999-12-30en_UK
local.rioxx.licencehttp://www.rioxx.net/licenses/under-embargo-all-rights-reserved||en_UK
local.rioxx.filenameCancer Res-2016-Yogev-3025-35.pdfen_UK
local.rioxx.filecount1en_UK
local.rioxx.source0008-5472en_UK
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