Seclidemstat blocks the transcriptional function of multiple FET-fusion oncoproteins.

Autor:	Rask GC; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43215, USA., Taslim C; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43215, USA., Bayanjargal A; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43215, USA.; Medical Scientist Training Program, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA., Cannon MV; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43215, USA., Selich-Anderson J; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43215, USA., Crow JC; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43215, USA., Duncan A; Salarius Pharmaceuticals, Houston, TX, 77021, USA., Theisen ER; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43215, USA.; Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 May 21. Date of Electronic Publication: 2024 May 21.
DOI:	10.1101/2024.05.19.594897
Abstrakt:	Genes encoding the RNA-binding proteins FUS, EWSR1, and TAF15 (FET proteins) are involved in chromosomal translocations in rare sarcomas. FET-rearranged sarcomas are often aggressive malignancies affecting patients of all ages. New therapies are needed. These translocations fuse the 5' portion of the FET gene with a 3' partner gene encoding a transcription factor (TF). The resulting fusion proteins are oncogenic TFs with a FET protein low complexity domain (LCD) and a DNA binding domain. FET fusion proteins have proven stubbornly difficult to target directly and promising strategies target critical co-regulators. One candidate is lysine specific demethylase 1 (LSD1). LSD1 is recruited by multiple FET fusions, including EWSR1::FLI1. LSD1 promotes EWSR1::FLI1 activity and treatment with the noncompetitive inhibitor SP-2509 blocks EWSR1::FLI1 transcriptional function. A similar molecule, seclidemstat (SP-2577), is currently in clinical trials for FET-rearranged sarcomas (NCT03600649). However, whether seclidemstat has pharmacological activity against FET fusions has not been demonstrated. Here, we evaluate the in vitro potency of seclidemstat against multiple FET-rearranged sarcoma cell lines, including Ewing sarcoma, desmoplastic small round cell tumor, clear cell sarcoma, and myxoid liposarcoma. We also define the transcriptomic effects of seclidemstat treatment and evaluated the activity of seclidemstat against FET fusion transcriptional regulation. Seclidemstat showed potent activity in cell viability assays across FET-rearranged sarcomas and disrupted the transcriptional function of all tested fusions. 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. Competing Interests: Disclosures: E.R.T. has received research funding in the past from Salarius Pharmaceuticals that is related to the work performed here. E.R.T. currently receives no research funding from Salarius Pharmaceuticals and has no financial stake in the company. A.D. declares competing interests as an employee of Salarius Pharmaceuticals during the time the project was being performed. No disclosures are reported by other authors.
Databáze:	MEDLINE
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