(P 261) EFFICACY OF BET INHIBITORS IN SOLITARY FIBROUS TUMOR: AN IN VITRO EVALUATION

Objective: Solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms driven by NAB2-STAT6 gene fusion. Currently, the therapeutic options available for advanced unresectable SFTs are limited to antiangiogenics, with cycles alternating different molecules. However, outcomes are still insufficient, with mainly temporal partial responses achieved. Thus, there is an urgent need for novel therapeutic approaches. Bromodomain and extra-terminal (BET) protein inhibitors have shown promising results in several types of cancers, including rhabdomyosarcoma, by targeting the transcription of genes regulated by BET proteins. We explore the potential effectiveness of BET inhibitors in SFT, as the role of targeted therapies in this entity has yet to be determined.

Methods: Three different BET inhibitors, Mivebresib, Pelabresib, and ABBV-744, were evaluated to determine their antitumor activity in SFT cell lines. The SFT models used in this study were INT-SFT (large-T antigen transformed) and IEC139 (primary). As non-translocated controls, we employed leiomyosarcoma cell lines, specifically CP0024 (primary) and SK-UT-1 (commercial). To assess the effects of BET inhibitors on SFT cell viability and death, different assays were conducted: cell viability assays using MTS colorimetry, flow cytometry apoptosis assays, and Western blot (WB) analysis.

Results: Our findings revealed that BET inhibitors reduced cell viability in SFT cell lines to a greater extent than in leiomyosarcoma, particularly Mivebresib (IC50 of 5.17x10-10, 1.91x10-9 vs 1.24x10-7, 2.86x10-8). Specificity for SFT was confirmed by flow cytometry apoptosis assays and increased expression of apoptosis markers (cleaved PARP-1) by WB. WB analysis demonstrated upregulation of γ-H2AX, a DNA-double strand break marker, and downregulation of RAD51, a protein involved in homologous recombination, suggesting a potential DNA damage-driven mechanism of action for BET inhibitors in SFTs. In addition, a synergistic effect was observed between BET inhibitors and Rucaparib, a commonly used PARP inhibitor (Combination Index of 0.42 and 0.27 for INT-SFT and IEC139 respectively).

Conclusion: BET inhibitors demonstrated efficacy and specificity for SFT in vitro models, potentially through targeting the HR pathway. Further investigations, including in vivo experiments, are necessary to elucidate the underlying mechanisms and evaluate clinical efficacy. The knowledge gained from these studies can lay the groundwork for potential clinical trials that will enable us to assess their safety, efficacy, and potential side effects in the context of SFT.