文章：

重新利用卡博赞替尼治疗KIT驱动的t（8;21）急性髓性白血病

Repurposing cabozantinib with therapeutic potential in KIT-driven t(8;21) acute myeloid leukaemias 

原文发布日期：2021-04-08 

英文摘要：

Cabozantinib is an orally available, multi-target tyrosine kinase inhibitor approved for the treatment of several solid tumours and known to inhibit KIT tyrosine kinase. In acute myeloid leukaemia (AML), aberrant KIT tyrosine kinase often coexists with t(8;21) to drive leukaemogenesis. Here we evaluated the potential therapeutic effect of cabozantinib on a selected AML subtype characterised by t(8;21) coupled with KIT mutation. Cabozantinib exerted substantial cytotoxicity in Kasumi-1 cells with an IC50 of 88.06 ± 4.32 nM, which was well within clinically achievable plasma levels. The suppression of KIT phosphorylation and its downstream signals, including AKT/mTOR, STAT3, and ERK1/2, was elicited by cabozantinib treatment and associated with subsequent alterations of cell cycle- and apoptosis-related molecules. Cabozantinib also disrupted the synthesis of an AML1-ETO fusion protein in a dose- and time-dependent manner. In a mouse xenograft model, cabozantinib suppressed tumourigenesis at 10 mg/kg and significantly prolonged survival of the mice. Further RNA-sequencing analysis revealed that mTOR-mediated signalling pathways were substantially inactivated by cabozantinib treatment, causing the downregulation of ribosome biogenesis and glycolysis, along with myeloid leukocyte activation. We suggest that cabozantinib may be effective in the treatment of AML with t(8;21) and KIT mutation. Relevant clinical trials are warranted. 

摘要翻译： 

卡博替尼是一种口服多靶点酪氨酸激酶抑制剂，已获批用于治疗多种实体瘤，其抑制KIT酪氨酸激酶的活性已得到明确认识。在急性髓系白血病（AML）中，KIT酪氨酸激酶异常常与t(8;21)易位共存并驱动白血病的发生。本研究旨在评估卡博替尼对具有t(8;21)易位伴KIT突变特定AML亚型的潜在治疗作用。卡博替尼对Kasumi-1细胞表现出显著细胞毒性，IC50值为88.06±4.32 nM，该浓度完全处于临床可达到的血药水平范围内。通过抑制KIT磷酸化及其下游信号通路（包括AKT/mTOR、STAT3和ERK1/2），卡博替尼处理引发了细胞周期和凋亡相关分子的系列改变。该药物还能以剂量和时间依赖性方式抑制AML1-ETO融合蛋白的合成。在小鼠异种移植模型中，10 mg/kg剂量的卡博替尼可有效抑制肿瘤发生并显著延长小鼠生存期。进一步的RNA测序分析显示，卡博替尼处理可实质性抑制mTOR介导的信号通路，导致核糖体生物合成和糖酵解过程下调，同时抑制髓系白细胞活化。本研究提示卡博替尼可能对伴有t(8;21)易位和KIT突变的AML具有治疗价值，有必要开展相关临床试验加以验证。

原文链接：

Repurposing cabozantinib with therapeutic potential in KIT-driven t(8;21) acute myeloid leukaemias