Cancers, especially fusion oncoprotein (FO)-driven hematological cancers and sarcomas, often develop from a low number of key mutations. Solitary Fibrous Tumor (SFT) is a rare mesenchymal tumor driven by the NAB2-STAT6 oncofusion gene. Currently, the treatment options for SFT remain limited, with anti-angiogenic drugs providing only partial responses and an average survival of two years. To address this challenge, we constructed SFT cell models harboring specific NAB2-STAT6 fusion transcripts using the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology. High-throughput drug screens demonstrated that the BET inhibitor Mivebresib can differentially reduce proliferation in SFT cell models. Subsequently, BET inhibitors Mivebresib and BMS-986158 efficiently reduced tumor growth in an SFT patient-derived xenograft (PDX) animal model. Furthermore, our data showed that NAB2-STAT6 fusions may lead to higher levels of DNA damage in SFTs. Consequently, combining BET inhibitors with PARP (Poly (ADP-ribose) polymerase) or ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells. Taken together, our study established BET inhibitors Mivebresib and BMS-986158 as promising anti-SFT agents.
Significance New therapies are a clinical need for patients with Solitary Fibrous Tumor. We demonstrated that BET inhibitors are highly active in the preclinical setting for the treatment of this sarcoma entity.
D.S.M. has received institutional research grants from PharmaMar and Synox outside the submitted work; travel support from PharmaMar, and personal fees from Tecnopharma, outside the submitted work. J.M.-B. has received honoraria for consulting or advisory board participation and expert testimony from PharmaMar, Bayer, GSK, Deciphera, Boehringer Ingelheim, Cogent Biosciences, Roche, Tecnofarma and Asofarma; and research funding for clinical studies (institutional) from Deciphera, PharmaMar, Eli Lilly and Company, BMS, Pfizer, Boehringer Ingelheim, Synox, ABBISKO, Biosplice, Lixte, Karyopharm, Rain Therapeutics, INHIBRX, Immunome, Philogen, Cebiotex, PTC Therapeutics, Inc. and SpringWorks therapeutics. The remaining authors declare no competing interests.
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