2. Academic Validation
  3. Abemaciclib impairs glioblastoma sphere formation by targeting the GSK3β-mediated transcriptional regulation of CD44 and TCF7L2

Abemaciclib impairs glioblastoma sphere formation by targeting the GSK3β-mediated transcriptional regulation of CD44 and TCF7L2

  • Cancer Gene Ther. 2025 Aug 14. doi: 10.1038/s41417-025-00955-z.
Muh-Lii Liang # 1 2,  Chun-Han Chen # 3 4 5,  Ya-Ching Lin 6,  Yu-Chen Lin 3 4,  Yun-Ru Liu 6,  Yi-Huei Ding 1,  Cheng-Ying Chu 7,  Tsung-Han Hsieh 8
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Mackay Memorial Hospital, Taipei, Taiwan, ROC.
  • 2 Department of Medicine, Mackay Medical College, Taipei, Taiwan, ROC.
  • 3 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
  • 4 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
  • 5 Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, ROC.
  • 6 Precision Health Center, Taipei Medical University, Taipei, Taiwan, ROC.
  • 7 CRISPR Gene Targeting Core, Taipei Medical University, Taipei, Taiwan, ROC.
  • 8 Precision Health Center, Taipei Medical University, Taipei, Taiwan, ROC. thhsieh@tmu.edu.tw.
  • # Contributed equally.
PMID: 40813896 DOI: 10.1038/s41417-025-00955-z
Abstract

Glioblastoma multiforme (GBM) is an aggressive brain tumor partly driven by Cancer Stem Cells (CSCs). Abemaciclib demonstrates the potential for treating GBM, although its mechanisms beyond RB phosphorylation are not fully understood. This study reveals that Abemaciclib diminishes GBM sphere formation by influencing EMT pathways via GSK3β-mediated regulation of CD44 and TCF7L2. Treatment with Abemaciclib significantly hindered sphere formation in GBM cells, and transcriptomic analysis indicated EMT pathways suppression. Mechanistically, Abemaciclib consistently lowered the expression of CD44 and TCF7L2 in both parental and sphere cells by inhibiting GSK3β phosphorylation. A pharmacological GSK3β inhibitor produced similar effects, reinforcing the existence of a GSK3β-CD44/TCF7L2 axis. Moreover, orthotopic xenografts confirmed reduced tumor growth and CD44 expression in vivo. Analyses of TCGA and CGGA datasets revealed that the mesenchymal GBM subtype (MES-GBM), linked with poor outcomes, exhibits elevated EMT gene expression. Treatment of MES-like LN229 cells with Abemaciclib resulted in decreased phosphorylation of GSK3β and reductions in EMT-related gene expression. Our findings highlight a novel EMT-suppressive action of Abemaciclib, illustrating its therapeutic potential for targeting the CSCs and for treating the MES-GBM. This research provides mechanistic insights and justification for repurposing Abemaciclib as targeted therapies for aggressive glioblastoma.

Figures
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  • HY-16297A
    99.97%, CDK4/6抑制剂
    CDK
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