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

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.

Desmoplastic small round cell tumor cancer stem cell-like cells resist chemotherapy but remain dependent on the EWSR1-WT1 oncoprotein

“…Intriguingly, these supplements, while not inhibitory, were dispensable for tumorsphere formation in DSRCT. This finding is concordant with a recent study that established the novel OV-054 DSRCT cell line and demonstrated the ability of this cell line to grow in suspension culture without the need for growth factor supplementation (Bleijs et al, 2021). Despite these differences in culture conditions, our DSRCT CSC-like model demonstrated similar increases in stemness markers as the CSCs in other cancer types, with stemness marker inductions ranging from 3-to 10-fold in comparison to adherent culture conditions (Walter et al, 2011;Magrath et al, 2020).…”

Enzalutamide Induces Cytotoxicity in Desmoplastic Small Round Cell Tumor Independent of the Androgen Receptor

“…Genes co-occupied by AR and EWSR1::WT1 included previously identified EWSR1::WT1 regulated targets MERTK, CCL25, and FGFR4 (Fig. 3B) 19,20 .…”

Highlighting the Diversity of Desmoplastic Small Round Cell Tumor: A Case Series

“…53 Effective therapeutic agents targeting downstream genes of the EWSR1::WT1 fusion are urgently needed to potentially improve outcomes for this highly aggressive tumor. 54 Therefore, a better understanding of this neoplasm is crucial to develop more effective treatments options. Correct identification of patients with DSRCT is critical to facilitate clinical trial enrollment and the study of new therapeutic protocols.…”