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Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as an Effective Therapy for

Justin W Magrath1, Shruthi Sanjitha Sampath1, Dane A Flinchum1

  • 1Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.

Cancer Research
|April 8, 2024
PubMed

Insights

EWSR1::WT1 drives pediatric sarcoma growth by upregulating the cyclin D-CDK4/6-RB pathway. Targeting this axis with palbociclib shows promise for treating desmoplastic small round cell tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pediatric Cancer Research

Background:

  • Desmoplastic small round cell tumors (DSRCT) are aggressive pediatric sarcomas with poor prognosis.
  • Current treatments are insufficient, with a 5-year survival rate of 15-25%.
  • The EWSR1::WT1 fusion oncogene is a hallmark of DSRCT, but targeted therapies are lacking.

Purpose of the Study:

  • To investigate the essentiality of EWSR1::WT1 in DSRCT.
  • To elucidate the molecular mechanisms by which EWSR1::WT1 drives tumor growth.
  • To evaluate the therapeutic potential of targeting the identified pathway with palbociclib.

Main Methods:

  • Depletion of EWSR1::WT1 in DSRCT models.
  • Transcriptomic analysis to identify EWSR1::WT1-mediated transcriptional alterations.
  • Analysis of EWSR1::WT1 binding to gene promoters, including CCND1.
  • Assessment of DSRCT xenograft models treated with palbociclib.

Main Results:

  • EWSR1::WT1 is essential for DSRCT growth in vivo.
  • EWSR1::WT1 induces unique transcriptional changes and directly upregulates gene expression.
  • The E-KTS isoform of EWSR1::WT1 promotes DSRCT growth via the cyclin D-CDK4/6-RB axis.
  • Palbociclib treatment significantly reduced tumor growth in DSRCT xenograft models.

Conclusions:

  • EWSR1::WT1 is a critical driver of DSRCT, acting through the cyclin D-CDK4/6-RB pathway.
  • Palbociclib effectively targets this pathway, demonstrating therapeutic potential for DSRCT.
  • These findings support the clinical investigation of palbociclib for treating desmoplastic small round cell tumors.

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