Seclidemstat blocks the transcriptional function of multiple FET-fusion oncoproteins

Genes encoding the RNA-binding proteins FUS, EWSR1, and TAF15 (FET proteins) are involved in chromosomal translocations in several rare sarcomas. FET-rearranged sarcomas are often aggressive malignancies affecting pediatric, adolescent, and young and middle-aged adults, with prognosis depending on the fusion and whether the disease is localized, metastatic, or relapsed. New therapies are needed for these patients. These translocations fuse the 5’ portion of the FET family gene with a 3’ partner gene encoding a transcription factor. The resulting fusion proteins have the intrinsically disordered low complexity domain (LCD) of the FET protein paired with a DNA binding domain and these chimeras function as oncogenic transcription factors. FET fusion proteins have proven stubbornly difficult to target directly and promising new therapeutic strategies target the critical regulators and co-regulators of these proteins. One such protein is the histone lysine specific demethylase 1 (LSD1). LSD1 physically interacts with and is recruited by multiple FET fusions, including EWSR1::FLI1. LSD1 promotes EWSR1::FLI1 gene regulation and prior studies showed that treatment with the noncompetitive inhibitor SP-2509 blocked the transcriptional activity of the fusion. A similar molecule, seclidemstat (SP-2577), was identified as a promising lead for clinical development and is currently in clinical trials for FET-rearranged sarcomas (NCT03600649). However, whether seclidemstat has pharmacological activity against EWSR1::FLI1 or any other FET fusion protein has yet to be demonstrated. In this study, we sought to evaluate the in vitro potency of seclidemstat against multiple cell lines derived from different FET-rearranged sarcomas, including Ewing sarcoma, desmoplastic small round cell tumor, clear cell sarcoma, and myxoid liposarcoma. We also defined the transcriptomic effect of seclidemstat treatment in these diseases and evaluated the activity of seclidemstat against FET fusion transcriptional regulation in multiple cell lines. Seclidemstat showed potent activity in cell viability assays in all four FET-rearranged sarcomas and disrupted the transcriptional function of all the tested fusion proteins. Though epigenetic and targeted inhibitors are unlikely to be effective as a single agents in the clinic, these data suggest seclidemstat remains a promising new treatment strategy for patients with FET-rearranged sarcomas