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GSK3-beta as a candidate therapeutic target in soft tissue sarcomas
S Verbeke1,2, R Perret3, V Chaire1,2
1Sarcoma Unit, Institut Bergonié, 229 cours de l'Argonne, 33000, Bordeaux, France.
Abstract:
Soft tissue sarcoma (STS) is a predominantly fatal rare malignancy with inadequate treatment options. Glycogen synthase kinase 3β (GSK-3β) is an emerging target in human malignancies. Its therapeutic relevance in STS is unknown. We analyzed the prognostic impact of GSK-3β gene and protein expression in two independent cohorts of patients with STS. We then treated STS cell lines and mice xenografts with a novel GSK-3 inhibitor 9-ING-41 alone or in combination with chemotherapy. We demonstrated that 9-ING-41 treatment induced significant STS cells apoptosis and was synergistic in vivo when combined with chemotherapy. Mechanistically, 9-ING-41 induces significant apoptosis of STS cells via suppression of NF-κB-mediated X-linked inhibitor of apoptosis protein (XIAP) expression. These data support the inclusion of patients with STS in clinical studies of 9-ING-41 alone and in combination with chemotherapy.
Insights
A novel drug targeting Glycogen synthase kinase 3 beta (GSK-3β) shows promise for treating soft tissue sarcoma (STS). This GSK-3β inhibitor effectively induced cancer cell death and enhanced chemotherapy effectiveness in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Soft tissue sarcoma (STS) is a rare, often fatal cancer with limited treatment options.
- Glycogen synthase kinase 3 beta (GSK-3β) is implicated in various cancers, but its role in STS is unclear.
- Investigating GSK-3β as a therapeutic target in STS is crucial.
Discussion:
- The study analyzed GSK-3β expression in STS patient cohorts to assess its prognostic significance.
- A novel GSK-3β inhibitor, 9-ING-41, was evaluated in STS cell lines and mouse xenografts.
- The inhibitor demonstrated efficacy in inducing apoptosis and synergizing with chemotherapy.
Key Insights:
- GSK-3β gene and protein expression correlate with prognosis in soft tissue sarcoma.
- The novel GSK-3β inhibitor 9-ING-41 effectively induces apoptosis in STS cells.
- 9-ING-41 exhibits synergistic effects when combined with conventional chemotherapy in vivo.
- The mechanism involves the suppression of NF-κB-mediated X-linked inhibitor of apoptosis protein (XIAP) expression.
Outlook:
- These findings support the clinical investigation of 9-ING-41 for STS treatment.
- Further research should explore 9-ING-41 in combination regimens for improved patient outcomes.
- The study highlights GSK-3β as a viable therapeutic target for soft tissue sarcoma.
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