HDAC and Proteasome Inhibitors Synergize to Activate Pro-Apoptotic Factors in Synovial Sarcoma
Aimée N Laporte1, Jared J Barrott2, Ren Jie Yao1
1Faculty of Medicine, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Abstract:
Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting its driving SS18-SSX fusion oncoprotein are currently available. Patients remain at high risk for early and late metastasis. A high-throughput drug screen consisting of over 900 tool compounds and epigenetic modifiers, representing over 100 drug classes, was undertaken in a panel of synovial sarcoma cell lines to uncover novel sensitizing agents and targetable pathways. Top scoring drug categories were found to be HDAC inhibitors and proteasomal targeting agents. We find that the HDAC inhibitor quisinostat disrupts the SS18-SSX driving protein complex, thereby reestablishing expression of EGR1 and CDKN2A tumor suppressors. In combination with proteasome inhibition, HDAC inhibitors synergize to decrease cell viability and elicit apoptosis. Quisinostat inhibits aggresome formation in response to proteasome inhibition, and combination treatment leads to elevated endoplasmic reticulum stress, activation of pro-apoptotic effector proteins BIM and BIK, phosphorylation of BCL-2, increased levels of reactive oxygen species, and suppression of tumor growth in a murine model of synovial sarcoma. This study identifies and provides mechanistic support for a particular susceptibility of synovial sarcoma to the combination of quisinostat and proteasome inhibition.
Insights
This study reveals that combining HDAC inhibitors like quisinostat with proteasome inhibitors effectively targets synovial sarcoma by disrupting the SS18-SSX oncoprotein, reducing tumor growth, and inducing cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Synovial sarcoma lacks targeted therapies, with conventional treatments offering limited efficacy.
- The SS18-SSX fusion oncoprotein drives tumor development, but no drugs currently target it.
- Patients face a high risk of metastasis, necessitating novel therapeutic strategies.
Purpose of the Study:
- To identify novel sensitizing agents and targetable pathways for synovial sarcoma through a high-throughput drug screen.
- To investigate the therapeutic potential of combining HDAC inhibitors and proteasome inhibitors in synovial sarcoma.
Main Methods:
- A high-throughput drug screen of over 900 compounds and epigenetic modifiers in synovial sarcoma cell lines.
- Investigated the effects of quisinostat (an HDAC inhibitor) and proteasome inhibitors on cancer cell viability, apoptosis, and tumor suppressor expression.
- Evaluated the combination therapy in a murine model of synovial sarcoma.
Main Results:
- HDAC inhibitors and proteasomal targeting agents emerged as top-scoring drug categories.
- Quisinostat disrupted the SS18-SSX complex, restoring tumor suppressor expression (EGR1, CDKN2A).
- Combination therapy synergistically decreased cell viability, induced apoptosis, reduced aggresome formation, elevated endoplasmic reticulum stress, and suppressed tumor growth in vivo.
Conclusions:
- Synovial sarcoma exhibits a specific vulnerability to the combination of quisinostat and proteasome inhibition.
- This combination therapy offers a promising strategy for treating synovial sarcoma by targeting the SS18-SSX oncoprotein and related pathways.
- Mechanistic insights support the development of this dual-drug approach for clinical translation.
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