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Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma

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 scree...

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Bibliographic Details
Main Authors: Brien, Gerard (Author) , Fröhling, Stefan (Author)
Format: Article (Journal)
Language:English
Published: 15 November 2018
In: eLife
Year: 2018, Volume: 7
ISSN:2050-084X
DOI:10.7554/eLife.41305
Online Access:Verlag, Volltext: https://doi.org/10.7554/eLife.41305
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Author Notes:Gerard L Brien, David Remillard, Junwei Shi, Matthew L Hemming, Jonathon Chabon, Kieran Wynne, Eugène T Dillon, Gerard Cagney, Guido Van Mierlo, Marijke P Baltissen, Michiel Vermeulen, Jun Qi, Stefan Fröhling, Nathanael S Gray, James E Bradner, Christopher R Vakoc, Scott A Armstrong

MARC

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520 |a 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. 
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