title: BET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells.
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.
authors.affiliation: St. Vincent's Institute, Fitzroy, 3065 VIC, Australia.|Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, 3065 VIC, Australia.
authors.forename: Emma K
authors.initials: EK
authors.lastname: Baker
authors.affiliation: St. Vincent's Institute, Fitzroy, 3065 VIC, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Taylor
authors.affiliation: St. Vincent's Institute, Fitzroy, 3065 VIC, Australia.
authors.forename: Ankita
authors.initials: A
authors.lastname: Gupte
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
authors.forename: Phillip P
authors.initials: PP
authors.lastname: Sharp
authors.affiliation: St. Vincent's Institute, Fitzroy, 3065 VIC, Australia.
authors.forename: Mannu
authors.initials: M
authors.lastname: Walia
authors.affiliation: St. Vincent's Institute, Fitzroy, 3065 VIC, Australia.|Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, 3065 VIC, Australia.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Walsh
authors.affiliation: 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.
authors.forename: Andrew Cw
authors.initials: AC
authors.lastname: Zannettino
authors.affiliation: St. Vincent's Institute, Fitzroy, 3065 VIC, Australia.|Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, 3065 VIC, Australia.
authors.forename: Alistair M
authors.initials: AM
authors.lastname: Chalk
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.|The University of Melbourne, Department of Medical Biology, 3010 VIC, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Burns
authors.affiliation: St. Vincent's Institute, Fitzroy, 3065 VIC, Australia.|Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, 3065 VIC, Australia.|ACRF Rational Drug Discovery Centre, St. Vincent's Institute, Fitzroy, 3065 VIC, Australia.
authors.forename: Carl R
authors.initials: CR
authors.lastname: Walkley
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001381:Azepines / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D000099169:Fos-Related Antigen 1
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D018844:Cyclin-Dependent Kinases; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D014230:Triazoles; D000099169:Fos-Related Antigen 1; C561695:(+)-JQ1 compound