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Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as a Novel Therapeutic for Desmoplastic Small Round Cell Tumor

ABSTRACT: Desmoplastic small round cell tumor (DSRCT) is an aggressive, pediatric tumor characterized by the EWSR1::WT1 oncogene. Targeted therapies have not been developed and multimodal therapy is insufficient, leading to a 5-year survival rate of only 15-25%. Here, we deplete EWSR1::WT1 in DSRCT and for the first time establish its essentiality in vivo. Through transcriptomic analysis, we discover novel mechanistic insights into EWSR1::WT1 functionality including the uniqueness of its transcriptional alterations, the direct role of EWSR1::WT1 binding in gene upregulation, and the dominant role of the one of its two isoforms in transcription. We show that the dominant isoform binds to the CCND1 promoter and stimulates DSRCT growth through the Cyclin D-CDK4/6-RB axis. Treatment with the CDK4/6 inhibitor palbociclib successfully reduced growth in two DSRCT xenograft models. Given palbociclib’s previous approval by the FDA for the treatment of breast cancer, we advance palbociclib as an exciting DSRCT therapy that warrants urgent clinical investigation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252051 | GEO | 2024/02/06

REPOSITORIES: GEO

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