2. Academic Validation
  3. Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma

Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma

  • Elife. 2018 Nov 15:7:e41305. doi: 10.7554/eLife.41305.
Gerard L Brien 1 2,  David Remillard 3 4,  Junwei Shi 5,  Matthew L Hemming 1 3,  Jonathon Chabon 1,  Kieran Wynne 6,  Eugène T Dillon 6,  Gerard Cagney 6,  Guido Van Mierlo 7,  Marijke P Baltissen 7,  Michiel Vermeulen 7,  Jun Qi 4,  Stefan Fröhling 8 9 10,  Nathanael S Gray 4,  James E Bradner 3,  Christopher R Vakoc 11,  Scott A Armstrong 1
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston Children's Hospital and Harvard Medical School, Boston, United States.
  • 2 Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
  • 3 Department of Medical Oncology, Dana Farber Cancer Institute, Boston Children's Hospital and Harvard Medical School, Boston, United States.
  • 4 Department of Cancer Biology, Dana Farber Cancer Institute, Boston Children's Hospital and Harvard Medical School, Boston, United States.
  • 5 Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
  • 6 School of Biomolecular and Biomedical Science and Conway Institute, University College Dublin, Dublin, Ireland.
  • 7 Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, Nijmegen, The Netherlands.
  • 8 German Cancer Consortium, Heidelberg, Germany.
  • 9 Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
  • 10 Division of Translational Oncology, National Center for Tumor Diseases Heidelberg and German Cancer Research Center, Heidelberg, Germany.
  • 11 Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
PMID: 30431433 DOI: 10.7554/eLife.41305
Abstract

Synovial sarcoma tumours contain a characteristic fusion protein, SS18-SSX, which drives disease development. Targeting oncogenic fusion proteins presents an attractive therapeutic opportunity. However, SS18-SSX has proven intractable for therapeutic intervention. Using a domain-focused CRISPR screen we identified the bromodomain of BRD9 as a critical functional dependency in synovial sarcoma. BRD9 is a component of SS18-SSX containing BAF complexes in synovial sarcoma cells; and integration of BRD9 into these complexes is critical for cell growth. Moreover BRD9 and SS18-SSX co-localize extensively on the synovial sarcoma genome. Remarkably, synovial sarcoma cells are highly sensitive to a novel small molecule degrader of BRD9, while Other sarcoma subtypes are unaffected. Degradation of BRD9 induces downregulation of oncogenic transcriptional programs and inhibits tumour progression in vivo. We demonstrate that BRD9 supports oncogenic mechanisms underlying the SS18-SSX fusion in synovial sarcoma and highlight targeted degradation of BRD9 as a potential therapeutic opportunity in this disease.

Keywords

BRD9; SS18-SSX; SWI/SNF; biochemistry; cancer biology; chemical biology; fusion protein; human; synovial sarcoma; targeted degradation.

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