Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization.

Autor:	Pedot G; Department of Oncology and Children's Research Center, University Children's Hospital, Steinwiesstrasse 32, 8032, Zurich, Switzerland., Marques JG; Department of Oncology and Children's Research Center, University Children's Hospital, Steinwiesstrasse 32, 8032, Zurich, Switzerland., Ambühl PP; Department of Oncology and Children's Research Center, University Children's Hospital, Steinwiesstrasse 32, 8032, Zurich, Switzerland., Wachtel M; Department of Oncology and Children's Research Center, University Children's Hospital, Steinwiesstrasse 32, 8032, Zurich, Switzerland., Kasper S; Department of Oncology and Children's Research Center, University Children's Hospital, Steinwiesstrasse 32, 8032, Zurich, Switzerland., Ngo QA; Department of Oncology and Children's Research Center, University Children's Hospital, Steinwiesstrasse 32, 8032, Zurich, Switzerland., Niggli FK; Department of Oncology and Children's Research Center, University Children's Hospital, Steinwiesstrasse 32, 8032, Zurich, Switzerland., Schäfer BW; Department of Oncology and Children's Research Center, University Children's Hospital, Steinwiesstrasse 32, 8032, Zurich, Switzerland. Electronic address: beat.schaefer@kispi.uzh.ch.
Jazyk:	angličtina
Zdroj:	Neoplasia (New York, N.Y.) [Neoplasia] 2022 May; Vol. 27, pp. 100784. Date of Electronic Publication: 2022 Mar 30.
DOI:	10.1016/j.neo.2022.100784
Abstrakt:	Oncogenic transcription factors lacking enzymatic activity or targetable binding pockets are typically considered "undruggable". An example is provided by the EWS-FLI1 oncoprotein, whose continuous expression and activity as transcription factor are critically required for Ewing sarcoma tumor formation, maintenance, and proliferation. Because neither upstream nor downstream targets have so far disabled its oncogenic potential, we performed a high-throughput drug screen (HTS), enriched for FDA-approved drugs, coupled to a Global Protein Stability (GPS) approach to identify novel compounds capable to destabilize EWS-FLI1 protein by enhancing its degradation through the ubiquitin-proteasome system. The protein stability screen revealed the dual histone deacetylase (HDAC) and phosphatidylinositol-3-kinase (PI3K) inhibitor called fimepinostat (CUDC-907) as top candidate to modulate EWS-FLI1 stability. Fimepinostat strongly reduced EWS-FLI1 protein abundance, reduced viability of several Ewing sarcoma cell lines and PDX-derived primary cells and delayed tumor growth in a xenograft mouse model, whereas it did not significantly affect healthy cells. Mechanistically, we demonstrated that EWS-FLI1 protein levels were mainly regulated by fimepinostat's HDAC activity. Our study demonstrates that HTS combined to GPS is a reliable approach to identify drug candidates able to modulate stability of EWS-FLI1 and lays new ground for the development of novel therapeutic strategies aimed to reduce Ewing sarcoma tumor progression. Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interests. (Copyright © 2022. Published by Elsevier Inc.)
Databáze:	MEDLINE
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