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Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma
Gerard L Brien1,2, David Remillard3,4, Junwei Shi5
1Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston Children's Hospital and Harvard Medical School, Boston, United States.
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.
Insights
Researchers identified BRD9 as a key dependency in synovial sarcoma, driven by the SS18-SSX fusion protein. Targeting BRD9 with a novel degrader shows promise for treating this cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Synovial sarcoma is driven by the SS18-SSX fusion protein, a challenging therapeutic target.
- Targeting oncogenic fusion proteins is a promising strategy for cancer treatment.
Purpose of the Study:
- To identify novel therapeutic targets in synovial sarcoma.
- To investigate the role of BRD9 in SS18-SSX driven oncogenesis.
Main Methods:
- A domain-focused CRISPR screen was employed to identify functional dependencies.
- The study utilized a novel small molecule degrader of BRD9.
- In vivo tumor progression assays were performed.
Main Results:
- The bromodomain of BRD9 was identified as a critical dependency in synovial sarcoma.
- BRD9 is essential for SS18-SSX containing BAF complexes and cell growth.
- Synovial sarcoma cells showed high sensitivity to a BRD9 degrader, unlike other sarcoma subtypes.
- BRD9 degradation downregulated oncogenic programs and inhibited tumor progression in vivo.
Conclusions:
- BRD9 is a crucial mediator of SS18-SSX oncogenic mechanisms in synovial sarcoma.
- Targeted degradation of BRD9 represents a potential therapeutic strategy for synovial sarcoma.
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