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BET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells

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dc.contributor.authorBaker, E.
dc.contributor.authorTaylor, S.
dc.contributor.authorGupte, A.
dc.contributor.authorSharp, P.
dc.contributor.authorWalia, M.
dc.contributor.authorWalsh, N.
dc.contributor.authorZannettino, A.
dc.contributor.authorChalk, A.
dc.contributor.authorBurns, C.
dc.contributor.authorWalkley, C.
dc.date.issued2015
dc.description.abstractOsteosarcoma (OS) survival rates have plateaued in part due to a lack of new therapeutic options. Here we demonstrate that bromodomain inhibitors (BETi), JQ1, I-BET151, I-BET762, exert potent anti-tumour activity against primary and established OS cell lines, mediated by inhibition of BRD4. Strikingly, unlike previous observations in long-term established human OS cell lines, the antiproliferative activity of JQ1 in primary OS cells was driven by the induction of apoptosis, not cell cycle arrest. In further contrast, JQ1 activity in OS was mediated independently of MYC downregulation. We identified that JQ1 suppresses the transcription factor FOSL1 by displacement of BRD4 from its locus. Loss of FOSL1 phenocopied the antiproliferative effects of JQ1, identifying FOSL1 suppression as a potential novel therapeutic approach for OS. As a monotherapy JQ1 demonstrated significant anti-tumour activity in vivo in an OS graft model. Further, combinatorial treatment approaches showed that JQ1 increased the sensitivity of OS cells to doxorubicin and induced potent synergistic activity when rationally combined with CDK inhibitors. The greater level of activity achieved with the combination of BETi with CDK inhibitors demonstrates the efficacy of this combination therapy. Taken together, our studies show that BET inhibitors are a promising new therapeutic for OS.
dc.description.statementofresponsibilityEmma K Baker, Scott Taylor, Ankita Gupte, Phillip P Sharp, Mannu Walia, Nicole C Walsh, Andrew CW Zannettino, Alistair M Chalk, Christopher J Burns, Carl R Walkley
dc.identifier.citationScientific Reports, 2015; 5(1):10120-1-10120-14
dc.identifier.doi10.1038/srep10120
dc.identifier.issn2045-2322
dc.identifier.issn2045-2322
dc.identifier.orcidZannettino, A. [0000-0002-6646-6167]
dc.identifier.urihttp://hdl.handle.net/2440/91242
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.grantNHMRC
dc.rightsThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
dc.source.urihttps://doi.org/10.1038/srep10120
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectOsteosarcoma
dc.subjectAzepines
dc.subjectTriazoles
dc.subjectCyclin-Dependent Kinases
dc.subjectProto-Oncogene Proteins c-fos
dc.subjectProto-Oncogene Proteins c-myc
dc.subjectTranscription Factors
dc.subjectAntineoplastic Agents
dc.subjectProtein Kinase Inhibitors
dc.subjectApoptosis
dc.subjectDown-Regulation
dc.subjectDrug Synergism
dc.subjectGene Knockdown Techniques
dc.subjectCell Cycle Checkpoints
dc.titleBET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells
dc.typeJournal article
pubs.publication-statusPublished

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