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.