Title: BET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells
Authors: Baker, EK
Taylor, S
Gupte, A
Sharp, PP
Walia, M
Walsh, NC
Zannettino, ACW
Chalk, AM
Burns, CJ
Walkley, CR
Issue Year: 2015
Publisher NATURE PUBLISHING GROUP
Series Sci Rep:
Abstract Osteosarcoma (OS) survival rates have plateaued in part due to a lack of new therapeutic options. Here we demonstrate that bromodomain inhibitors (BETi), JQ(1), 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 JQ(1) in primary OS cells was driven by the induction of apoptosis, not cell cycle arrest. In further contrast, JQ(1) activity in OS was mediated independently of MYC downregulation. We identified that JQ(1) suppresses the transcription factor FOSL1 by displacement of BRD4 from its locus. Loss of FOSL1 phenocopied the antiproliferative effects of JQ(1), identifying FOSL1 suppression as a potential novel therapeutic approach for OS. As a monotherapy JQ(1) demonstrated significant anti-tumour activity in vivo in an OS graft model. Further, combinatorial treatment approaches showed that JQ(1) 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.
URI: https://publications.svi.edu.au/publications/2314
ISSN
Other Identifiers 10.1038/srep10120
Publication type Article