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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Oncogenic transcription factors like EWS-FLI1 are often "undruggable" due to lack of enzymatic activity or binding pockets.
• EWS-FLI1 is essential for Ewing sarcoma development, maintenance, and proliferation.
• Existing therapies targeting upstream or downstream molecules have not fully disabled EWS-FLI1's oncogenic potential.

Purpose of the Study:

• To identify novel compounds that destabilize the EWS-FLI1 oncoprotein using a high-throughput drug screen (HTS) combined with a Global Protein Stability (GPS) approach.
• To explore therapeutic strategies for Ewing sarcoma by targeting EWS-FLI1 protein degradation via the ubiquitin-proteasome system.

Main Methods:

• Performed HTS enriched for FDA-approved drugs coupled with GPS to screen for compounds enhancing EWS-FLI1 degradation.
• Utilized Ewing sarcoma cell lines and patient-derived xenograft (PDX) models for in vitro and in vivo validation.
• Investigated the mechanism of action, focusing on the role of histone deacetylase (HDAC) activity.

Main Results:

• Identified fimepinostat (CUDC-907), a dual histone deacetylase (HDAC) and phosphatidylinositol-3-kinase (PI3K) inhibitor, as a top candidate.
• Fimepinostat significantly reduced EWS-FLI1 protein levels, decreased Ewing sarcoma cell viability, and delayed tumor growth in a xenograft model.
• Fimepinostat demonstrated selectivity, with minimal impact on healthy cells, and its primary mechanism involved HDAC activity regulating EWS-FLI1 stability.

Conclusions:

• HTS combined with GPS is a viable strategy for discovering drugs that modulate the stability of challenging oncoproteins like EWS-FLI1.
• Fimepinostat shows promise as a therapeutic agent for Ewing sarcoma by targeting EWS-FLI1 degradation.
• This research opens new avenues for developing innovative treatments to combat Ewing sarcoma progression.