Hepatology:环素依赖性激酶5抑制剂,可改善索拉非尼在肝癌治疗中的反应:一种新的治疗策略

2018-07-30 MedSci MedSci原创

Cdk5抑制是改善索拉非尼治疗反应和防止索拉非尼治疗在肝癌中的逃逸的有效途径。值得注意的是,Cdk5是一种可寻址的靶点,经常在HCC中过表达;而使用Dinaciclib -临床测试的Cdk5抑制剂,很容易获得。研究为临床评价索拉非尼与Dinaciclib联合治疗晚期肝癌的疗效提供了依据。

研究背景:晚期肝癌(HCC)患者的治疗选择非常有限。唯一被批准的一线治疗是多酪氨酸激酶抑制剂索拉非尼,反应率低,副作用严重。特别是生长因子受体的代偿性激活导致了化学抗性,限制了索拉非尼的临床影响。然而,改善索拉非尼的联合方法失败了。本研究调查了环素依赖性激酶5 (Cdk5)的抑制剂作为一种很有前途的组合策略来改善索拉非尼在肝癌中的反应的效果。

研究方法和结果:索拉非尼与Cdk5抑制(shRNA或CRISPR/Cas9的基因敲除和药理学抑制剂)联合治疗,在体外和体内抑制了肿瘤细胞增殖和迁移,协同损害肝癌进展。重要的是,这些效应是由Cdk5的一种新机制介导的,基于LC-MS/MS的蛋白质组学方法显示,Cdk5抑制干扰细胞内运输,这个过程对于细胞稳态和生长因子受体信号非常重要。Cdk5的抑制导致核膜区增大的囊泡和相应的物质堆积,严重影响生长因子受体信号的范围和质量。因此,Cdk5抑制为全局干扰生长因子受体信号提供了一种全面的方法,这种方法优于单独抑制生长因子受体。

研究结论:Cdk5抑制是改善索拉非尼治疗反应和防止索拉非尼治疗在肝癌中的逃逸的有效途径。值得注意的是,Cdk5是一种可寻址的靶点,经常在HCC中过表达;而使用Dinaciclib -临床测试的Cdk5抑制剂,很容易获得。研究为临床评价索拉非尼与Dinaciclib联合治疗晚期肝癌的疗效提供了依据。

原始出处:

Ardelt MA, Frohlich T, Martini E, et al. Inhibition of Cyclin-dependent Kinase 5 - a Novel Strategy to Improve Sorafenib Response in HCC Therapy. Hepatology, 2018, Jul 23. doi: 10.1002/hep.30190.

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    2019-05-31 jklm09
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    2018-08-01 gwc384
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    2018-08-01 redcrab