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Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as an Effective Therapy for Desmoplastic Small Round Cell Tumors.
Magrath, Justin W; Sampath, Shruthi Sanjitha; Flinchum, Dane A; Hartono, Alifiani B; Goldberg, Ilon N; Boehling, Julia R; Savkovic, Suzana D; Lee, Sean B.
Afiliación
  • Magrath JW; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
  • Sampath SS; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
  • Flinchum DA; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
  • Hartono AB; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
  • Goldberg IN; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
  • Boehling JR; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
  • Savkovic SD; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
  • Lee SB; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Cancer Res ; 84(9): 1426-1442, 2024 May 02.
Article en En | MEDLINE | ID: mdl-38588409
ABSTRACT
Desmoplastic small round cell tumors (DSRCT) are a type of aggressive, pediatric sarcoma characterized by the EWSR1WT1 fusion oncogene. Targeted therapies for DSRCT have not been developed, and standard multimodal therapy is insufficient, leading to a 5-year survival rate of only 15% to 25%. Here, we depleted EWSR1WT1 in DSRCT and established its essentiality in vivo. Transcriptomic analysis revealed that EWSR1WT1 induces unique transcriptional alterations compared with WT1 and other fusion oncoproteins and that EWSR1WT1 binding directly mediates gene upregulation. The E-KTS isoform of EWSR1WT1 played a dominant role in transcription, and it bound to the CCND1 promoter and stimulated 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. As palbociclib has been approved by the FDA for the treatment of breast cancer, these findings demonstrate the sensitivity of DSRCT to palbociclib and support immediate clinical investigation of palbociclib for treating this aggressive pediatric cancer.

SIGNIFICANCE:

EWSR1WT1 is essential for desmoplastic small round cell tumors and upregulates the cyclin D-CDK4/6-RB axis that can be targeted with palbociclib, providing a targeted therapeutic strategy for treating this deadly tumor type.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperazinas / Piridinas / Proteínas de Fusión Oncogénica / Ensayos Antitumor por Modelo de Xenoinjerto / Proteína EWS de Unión a ARN / Quinasa 4 Dependiente de la Ciclina / Quinasa 6 Dependiente de la Ciclina / Tumor Desmoplásico de Células Pequeñas Redondas Límite: Animals / Humans Idioma: En Revista: Cancer Res Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperazinas / Piridinas / Proteínas de Fusión Oncogénica / Ensayos Antitumor por Modelo de Xenoinjerto / Proteína EWS de Unión a ARN / Quinasa 4 Dependiente de la Ciclina / Quinasa 6 Dependiente de la Ciclina / Tumor Desmoplásico de Células Pequeñas Redondas Límite: Animals / Humans Idioma: En Revista: Cancer Res Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos