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.
Highlights
Synovial sarcoma is an aggressive, high-grade soft tissue tumor arising most frequently in the extremities of adolescents and young adults [1]
We have shown that SS18-SSX acts as a bridge connecting activating transcription factor 2 (ATF2) to transducin-like enhancer of split 1 (TLE1), proteins which otherwise do not associate [9]
In order to identify drugs effectively targeting synovial sarcoma, a 900 compound highthroughput drug screen representing over 100 drug classes at a concentration of ~1 μM was undertaken in six synovial sarcoma cell lines: SYO-1 (SS18-SSX2), FUJI (SS18-SSX2), Yamato-SS (SS18-SSX1), ASKA-SS (SS18-SSX1), MoJo (SS18-SSX1) and SSR3A1, as well as negative control cell lines HEK293T and MCF7
Summary
Synovial sarcoma is an aggressive, high-grade soft tissue tumor arising most frequently in the extremities of adolescents and young adults [1]. Conventional cytotoxic therapy, including doxorubicin and ifosphamide, provides limited benefit. Patients remain at high risk for both early and late metastases, and despite best available therapies the mortality rate remains approximately 50% within 10 years of diagnosis [2]. Synovial sarcoma is characterized by a fusion oncogene derived from the chromosomal translocation t(X;18)(p11.2;q11.2) [3]. This translocation results in the fusion of the N-. PLOS ONE | DOI:10.1371/journal.pone.0169407 January 5, 2017
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