Seclidemstat blocks the transcriptional function of multiple FET-fusion oncoproteins
The FET family of RNA-binding proteins, including FUS, EWSR1, and TAF15, are implicated in chromosomal translocations found in rare and often aggressive sarcomas affecting individuals across all age groups. There is a pressing need for new therapies for these malignancies. These translocations result in fusion proteins, combining the 5′ portion of the FET gene with a 3′ region from a partner gene encoding a transcription factor (TF). The resulting oncogenic TFs contain a FET protein low complexity domain (LCD) and a DNA-binding domain. Direct targeting of FET fusion proteins has been challenging, and promising therapeutic strategies focus on inhibiting key co-regulators. One such target is lysine-specific demethylase 1 (LSD1), which is recruited by several FET fusion proteins, including EWSR1::FLI1. LSD1 enhances the activity of EWSR1::FLI1, and its inhibition by SP-2509 blocks EWSR1::FLI1 transcriptional function. A related compound, seclidemstat (SP-2577), is currently undergoing clinical trials for FET-rearranged sarcomas (NCT03600649), though its pharmacological efficacy against FET fusions has not been fully established.
In this study, we assessed the in vitro efficacy of seclidemstat in several FET-rearranged sarcoma cell lines, including Ewing sarcoma, desmoplastic small round cell tumor, clear cell sarcoma, and myxoid liposarcoma. We also examined the transcriptomic effects of seclidemstat treatment and its impact on FET fusion transcriptional regulation. Seclidemstat demonstrated potent activity in cell viability assays across various FET-rearranged sarcoma types and disrupted the transcriptional functions of the tested fusion proteins. While epigenetic and targeted inhibitors are unlikely to be effective as standalone treatments in clinical settings, these findings suggest that seclidemstat holds promise as a therapeutic strategy for patients with FET-rearranged sarcomas.