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Sci Rep. 2015 May 6;5:10120. doi: 10.1038/srep10120.

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

Author information

1
St. Vincent's Institute, Fitzroy, 3065 VIC, Australia.
2
Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, 3065 VIC, Australia.
3
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
4
Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide, SA 5005, Australia and Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.
5
The University of Melbourne, Department of Medical Biology, 3010 VIC, Australia.
6
ACRF Rational Drug Discovery Centre, St. Vincent's Institute, Fitzroy, 3065 VIC, Australia.

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.

PMID:
25944566
PMCID:
PMC4421868
DOI:
10.1038/srep10120
[Indexed for MEDLINE]
Free PMC Article

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