EWSR1-WT1 Target Genes and Therapeutic Options Identified in a Novel DSRCT In Vitro Model

SIMPLE SUMMARY: Desmoplastic small round cell tumor (DSRCT) is an extremely rare soft tissue sarcoma arising in the abdomen of adolescents and young adults. This sarcoma is driven by a single genomic rearrangement, resulting in the expression of the EWSR1-WT1 fusion gene. No effective treatment exists for DSRCT patients, which highlights the need for preclinical models to study disease progression and drug sensitivity. The aim of this study is to develop a pre-clinical DSRCT in vitro model, which enables investigating the molecular target genes of the EWSR1-WT1 fusion gene and allows for medium-throughput drug screening to discover new therapeutic options. ABSTRACT: Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft tissue sarcoma with a lack of effective treatment options and a poor prognosis. DSRCT is characterized by a chromosomal translocation, resulting in the EWSR1-WT1 gene fusion. The molecular mechanisms driving DSRCT are poorly understood, and a paucity of preclinical models hampers DSRCT research. Here, we establish a novel primary patient-derived DSRCT in vitro model, recapitulating the original tumor. We find that EWSR1-WT1 expression affects cell shape and cell survival, and we identify downstream target genes of the EWSR1-WT1 fusion. Additionally, this preclinical in vitro model allows for medium-throughput drug screening. We discover sensitivity to several drugs, including compounds targeting RTKs. MERTK, which has been described as a therapeutic target for several malignancies, correlates with EWSR1-WT1 expression. Inhibition of MERTK with the small-molecule inhibitor UNC2025 results in reduced proliferation of DSRCT cells in vitro, suggesting MERTK as a therapeutic target in DSRCT. This study underscores the usefulness of preclinical in vitro models for studying molecular mechanisms and potential therapeutic options.