Seclidemstat (SP-2577) induces transcriptomic reprogramming and cytotoxicity in multiple fusion-positive sarcomas

Genes encoding the RNA-binding proteins FUS, EWSR1, and TAF15 (FET proteins) are involved in chromosomal translocations in rare sarcomas. The encoded fusion oncoproteins typically include a DNA binding domain and function as oncogenic transcription factors. FET-rearranged sarcomas are often aggressive malignancies affecting patients of all ages. Oncogenic fusion TFs are challenging to target directly and new therapies are needed. Treatment with the small molecule SP-2509 results in reversal of the transcriptional activity of the FET fusion that causes Ewing sarcoma, EWSR1::FLI1. A similar molecule, seclidemstat (SP-2577), is currently in clinical trials for FET-rearranged sarcomas (NCT03600649), but its pharmacological activity in FET fusion positive sarcomas has not been demonstrated. We found potent seclidemstat cytotoxicity against both FET-rearranged and other fusion-positive sarcoma cell lines in vitro, including Ewing sarcoma, desmoplastic small round cell tumor, clear cell sarcoma, myxoid liposarcoma, and fusion-positive rhabdomyosarcoma. We also define transcriptomic effects of seclidemstat with bulk RNA-seq. Seclidemstat recapitulated much of SP-2509 transcriptional activity in Ewing sarcoma. Widespread transcriptional changes were seen in all tested cell lines after seclidemstat treatment, regardless of the fusion protein expressed. This included reversal of FET-fusion transcriptional signatures for EWSR1::WT1, EWSR1::ATF1, and EWSR1::ERG. Though novel inhibitors are unlikely to display single-agent efficacy in the clinic, these data suggest seclidemstat remains a promising new treatment strategy for patients with FET-rearranged and other fusion positive sarcomas.