GSK3-beta as a candidate therapeutic target in soft tissue sarcomas

Journal of Hematology & Oncology

L. Cavalcante¹  F. Giles¹  R. Perret²  V. Velasco²  E. Richard³  V. Chaire⁴  S. Verbeke⁴  A. Italiano⁵ 

[1] Actuate Therapeutics, Fort Worth, TX, USA;Department of Pathology, Institut Bergonié, Bordeaux, France;INSERM, U1218, Bordeaux, France;Sarcoma Unit, Institut Bergonié, 229 cours de l’Argonne, 33000, Bordeaux, France;INSERM, U1218, Bordeaux, France;Sarcoma Unit, Institut Bergonié, 229 cours de l’Argonne, 33000, Bordeaux, France;INSERM, U1218, Bordeaux, France;Faculty of Medicine, University of Bordeaux, Bordeaux, France;

关键词: Glycogen synthase kinase 3β;    Soft tissue sarcomas;    9-ING-41;   

DOI  :  10.1186/s13045-021-01215-x

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY