dc.contributor.author | Vaughan, L | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | Barker, K | |
dc.contributor.author | Chanthery, Y | |
dc.contributor.author | Gustafson, CW | |
dc.contributor.author | Tucker, E | |
dc.contributor.author | Renshaw, J | |
dc.contributor.author | Raynaud, F | |
dc.contributor.author | Li, X | |
dc.contributor.author | Burke, R | |
dc.contributor.author | Jamin, Y | |
dc.contributor.author | Robinson, SP | |
dc.contributor.author | Pearson, A | |
dc.contributor.author | Maira, M | |
dc.contributor.author | Weiss, WA | |
dc.contributor.author | Workman, P | |
dc.contributor.author | Chesler, L | |
dc.date.accessioned | 2016-12-07T14:51:42Z | |
dc.date.issued | 2016-09-06 | |
dc.identifier.citation | Oncotarget, 2016, 7 (36), pp. 57525 - 57544 | |
dc.identifier.issn | 1949-2553 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/316 | |
dc.identifier.eissn | 1949-2553 | |
dc.identifier.doi | 10.18632/oncotarget.10544 | |
dc.description.abstract | MYC oncoproteins deliver a potent oncogenic stimulus in several human cancers, making them major targets for drug development, but efforts to deliver clinically practical therapeutics have not yet been realized. In childhood cancer, aberrant expression of MYC and MYCN genes delineates a group of aggressive tumours responsible for a major proportion of pediatric cancer deaths. We designed a chemical-genetic screen that identifies compounds capable of enhancing proteasomal elimination of MYCN oncoprotein. We isolated several classes of compound that selectively kill MYCN expressing cells and we focus on inhibitors of PI3K/mTOR pathway in this study. We show that PI3K/mTOR inhibitors selectively killed MYCN-expressing neuroblastoma tumor cells, and induced significant apoptosis of transgenic MYCN-driven neuroblastoma tumors concomitant with elimination of MYCN protein in vivo. Mechanistically, the ability of these compounds to degrade MYCN requires complete blockade of mTOR but not PI3 kinase activity and we highlight NVP-BEZ235 as a PI3K/mTOR inhibitor with an ideal activity profile. These data establish that MYCN expression is a marker indicative of likely clinical sensitivity to mTOR inhibition, and provide a rationale for the selection of clinical candidate MYCN-destabilizers likely to be useful for the treatment of MYCN-driven cancers. | |
dc.format | Print | |
dc.format.extent | 57525 - 57544 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | IMPACT JOURNALS LLC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Mice, Transgenic | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Mice, Nude | |
dc.subject | Neuroblastoma | |
dc.subject | Imidazoles | |
dc.subject | Quinolines | |
dc.subject | Neoplasm Transplantation | |
dc.subject | Signal Transduction | |
dc.subject | Apoptosis | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Phosphorylation | |
dc.subject | Transgenes | |
dc.subject | Phosphatidylinositol 3-Kinases | |
dc.subject | HEK293 Cells | |
dc.subject | TOR Serine-Threonine Kinases | |
dc.subject | Glycogen Synthase Kinase 3 beta | |
dc.subject | N-Myc Proto-Oncogene Protein | |
dc.subject | Mechanistic Target of Rapamycin Complex 1 | |
dc.subject | Mechanistic Target of Rapamycin Complex 2 | |
dc.title | Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-06-01 | |
rioxxterms.versionofrecord | 10.18632/oncotarget.10544 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Oncotarget | |
pubs.issue | 36 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design | |
pubs.publication-status | Published | |
pubs.volume | 7 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Signal Transduction & Molecular Pharmacology | |
icr.researchteam | Paediatric Solid Tumour Biology and Therapeutics | |
icr.researchteam | Pre-Clinical MRI | |
icr.researchteam | Hit Discovery & Structural Design | |
dc.contributor.icrauthor | Clarke, Paul | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Burke, Rosemary | |
dc.contributor.icrauthor | Jamin, Yann | |
dc.contributor.icrauthor | Robinson, Simon | |
dc.contributor.icrauthor | Workman, Paul | |
dc.contributor.icrauthor | Chesler, Louis | |