دورية أكاديمية
أعرض في EDS

Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as an Effective Therapy for Desmoplastic Small Round Cell Tumors.

التفاصيل البيبلوغرافية
العنوان: Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as an Effective Therapy for Desmoplastic Small Round Cell Tumors.
المؤلفون: 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.
المصدر: Cancer research [Cancer Res] 2024 May 02; Vol. 84 (9), pp. 1426-1442.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Publication: Baltimore, Md. : American Association for Cancer Research
Original Publication: Chicago [etc.]
مواضيع طبية MeSH: Cyclin-Dependent Kinase 4*/antagonists & inhibitors , Cyclin-Dependent Kinase 4*/genetics , Cyclin-Dependent Kinase 6*/antagonists & inhibitors , Cyclin-Dependent Kinase 6*/genetics , Desmoplastic Small Round Cell Tumor*/genetics , Desmoplastic Small Round Cell Tumor*/drug therapy , Desmoplastic Small Round Cell Tumor*/pathology , Desmoplastic Small Round Cell Tumor*/metabolism , Oncogene Proteins, Fusion*/genetics , Oncogene Proteins, Fusion*/metabolism , Piperazines*/pharmacology , Piperazines*/therapeutic use , Pyridines*/pharmacology , Pyridines*/therapeutic use , RNA-Binding Protein EWS*/genetics , RNA-Binding Protein EWS*/metabolism , Xenograft Model Antitumor Assays*, Animals ; Humans ; Mice ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; WT1 Proteins/genetics ; WT1 Proteins/metabolism ; Mice, Inbred NOD
مستخلص: Desmoplastic small round cell tumors (DSRCT) are a type of aggressive, pediatric sarcoma characterized by the EWSR1::WT1 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 EWSR1::WT1 in DSRCT and established its essentiality in vivo. Transcriptomic analysis revealed that EWSR1::WT1 induces unique transcriptional alterations compared with WT1 and other fusion oncoproteins and that EWSR1::WT1 binding directly mediates gene upregulation. The E-KTS isoform of EWSR1::WT1 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: EWSR1::WT1 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.
(©2024 The Authors; Published by the American Association for Cancer Research.)
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معلومات مُعتمدة: R01 CA222856 United States CA NCI NIH HHS
المشرفين على المادة: EC 2.7.11.22 (CDK4 protein, human)
EC 2.7.11.22 (CDK6 protein, human)
EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
EC 2.7.11.22 (Cyclin-Dependent Kinase 6)
0 (EWSR1 protein, human)
0 (Oncogene Proteins, Fusion)
G9ZF61LE7G (palbociclib)
0 (Piperazines)
0 (Protein Kinase Inhibitors)
0 (Pyridines)
0 (RNA-Binding Protein EWS)
0 (WT1 protein, human)
0 (WT1 Proteins)
تواريخ الأحداث: Date Created: 20240408 Date Completed: 20240502 Latest Revision: 20240507
رمز التحديث: 20240508
مُعرف محوري في PubMed: PMC11063761
DOI: 10.1158/0008-5472.CAN-23-3334
PMID: 38588409
قاعدة البيانات: MEDLINE
الوصف
تدمد:1538-7445
DOI:10.1158/0008-5472.CAN-23-3334