Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/91242
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Type: Journal article
Title: BET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells
Author: Baker, E.
Taylor, S.
Gupte, A.
Sharp, P.
Walia, M.
Walsh, N.
Zannettino, A.
Chalk, A.
Burns, C.
Walkley, C.
Citation: Scientific reports, 2015; 5(1):10120-1-10120-14
Publisher: Nature Publishing Group
Issue Date: 2015
ISSN: 2045-2322
2045-2322
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Responsibility: 
Emma 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
Abstract: Osteosarcoma (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.
Keywords: Cell Line, Tumor; Animals; Humans; Mice; Osteosarcoma; Azepines; Triazoles; Cyclin-Dependent Kinases; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-myc; Transcription Factors; Antineoplastic Agents; Protein Kinase Inhibitors; Apoptosis; Down-Regulation; Drug Synergism; Gene Knockdown Techniques; Cell Cycle Checkpoints
Rights: This 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/
RMID: 0030028736
DOI: 10.1038/srep10120
Appears in Collections:Physiology publications

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