# Identification of BET inhibitors (BETi) against solitary fibrous tumor (SFT) through high-throughput screening (HTS)

## TL;DR

This study identifies BET inhibitors as potential treatments for a rare tumor called solitary fibrous tumor by using high-throughput screening and animal models.

## Contribution

The study introduces BET inhibitors as a novel therapeutic strategy for treating solitary fibrous tumor.

## Key findings

- BET inhibitors Mivebresib and BMS-986158 reduced SFT cell proliferation and tumor growth in animal models.
- NAB2-STAT6 fusions in SFTs may cause high DNA damage, making them sensitive to combination therapies with PARP or ATR inhibitors.
- Combining BET inhibitors with PARP or ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells.

## Abstract

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 with an average survival of two years. We constructed SFT cell models harboring specific NAB2-STAT6 fusion transcripts using the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology, and we used these cells as models of SFT. 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 high levels of DNA damage in SFTs. Consequently, combining BET inhibitors with PARP (Poly (ADP-ribose) polymerase) inhibitors or with ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells. Taken together, this study establishes BET inhibitors Mivebresib and BMS-986158 as promising anti-SFT agents.