Sarcoma Unit, Institut Bergonié, 229 cours de l'Argonne, 33000, Bordeaux, France.
INSERM, U1218, Bordeaux, France.
J Hematol Oncol. 2021 Dec 2;14(1):202. doi: 10.1186/s13045-021-01215-x.
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.
软组织肉瘤（STS）是一种主要致命的罕见恶性肿瘤，治疗选择有限。糖原合成酶激酶 3β（GSK-3β）是人类恶性肿瘤中的一个新兴靶点。其在 STS 中的治疗相关性尚不清楚。我们分析了 GSK-3β 基因和蛋白表达在两个独立 STS 患者队列中的预后影响。然后，我们用一种新型 GSK-3 抑制剂 9-ING-41 单独或联合化疗治疗 STS 细胞系和小鼠异种移植瘤。我们证明 9-ING-41 治疗诱导了 STS 细胞的显著凋亡，并且与化疗联合具有协同作用。在机制上，9-ING-41 通过抑制 NF-κB 介导的凋亡抑制蛋白（XIAP）的表达诱导 STS 细胞的显著凋亡。这些数据支持将 STS 患者纳入 9-ING-41 单独和联合化疗的临床试验。
