In:
eLife, eLife Sciences Publications, Ltd, Vol. 7 ( 2018-11-15)
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.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.41305.001
DOI:
10.7554/eLife.41305.002
DOI:
10.7554/eLife.41305.004
DOI:
10.7554/eLife.41305.005
DOI:
10.7554/eLife.41305.006
DOI:
10.7554/eLife.41305.007
DOI:
10.7554/eLife.41305.003
DOI:
10.7554/eLife.41305.008
DOI:
10.7554/eLife.41305.014
DOI:
10.7554/eLife.41305.015
DOI:
10.7554/eLife.41305.016
DOI:
10.7554/eLife.41305.017
DOI:
10.7554/eLife.41305.009
DOI:
10.7554/eLife.41305.010
DOI:
10.7554/eLife.41305.011
DOI:
10.7554/eLife.41305.012
DOI:
10.7554/eLife.41305.013
DOI:
10.7554/eLife.41305.018
DOI:
10.7554/eLife.41305.019
DOI:
10.7554/eLife.41305.020
DOI:
10.7554/eLife.41305.023
DOI:
10.7554/eLife.41305.021
DOI:
10.7554/eLife.41305.022
DOI:
10.7554/eLife.41305.024
DOI:
10.7554/eLife.41305.029
DOI:
10.7554/eLife.41305.030
DOI:
10.7554/eLife.41305.031
DOI:
10.7554/eLife.41305.025
DOI:
10.7554/eLife.41305.026
DOI:
10.7554/eLife.41305.027
DOI:
10.7554/eLife.41305.028
DOI:
10.7554/eLife.41305.032
DOI:
10.7554/eLife.41305.033
DOI:
10.7554/eLife.41305.034
DOI:
10.7554/eLife.41305.035
DOI:
10.7554/eLife.41305.036
DOI:
10.7554/eLife.41305.037
DOI:
10.7554/eLife.41305.038
DOI:
10.7554/eLife.41305.039
DOI:
10.7554/eLife.41305.043
DOI:
10.7554/eLife.41305.044
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2018
detail.hit.zdb_id:
2687154-3