Blood:靶向GCK通路:治疗RAS突变型MM的一种新选择性

2020-10-11 星云 MedSci原创

在高达50%的新确诊的多发性骨髓瘤(MM)患者中发现了NRAS、KRAS或BRAF的频发突变。大多数NRAS、KRAS和BRAF突变发生在热点区域,导致相应蛋白发生组成性激活。因此,靶向MM中的RAS

在高达50%的新确诊的多发性骨髓瘤(MM)患者中发现了NRAS、KRAS或BRAF的频发突变。大多数NRAS、KRAS和BRAF突变发生在热点区域,导致相应蛋白发生组成性激活。因此,靶向MM中的RAS突变将提高治疗效率,并有可能克服耐药性。

研究人员发现,生发中心激酶(GCK)是RAS突变型MM的一个新的治疗靶点

敲除GCK基因的MM细胞的体内外实验结果表明,沉默GCK可抑制MM细胞的生长,阻滞MKK4/7-JNK的磷酸化和并可影响IKZF1/3、BCL-6和c-MYC的降解。这些效应是通过过表达一种shRNA抗性的GCK来挽救,从而排除了GCK基因敲除的潜在的非靶点效应。

相反,过表达shRNA抗性的GCK激酶死亡突变体(K45A)可抑制MM细胞的增殖,不能挽救GCK基因敲除对MM细胞生长的抑制作用,表明GCK激酶活性在调节MM细胞的增殖和存活中起关键作用。

重要的是,RASMut细胞对GCK基因敲除的高敏感性表明,靶向GCK对携带RAS突变的MM是有效的。GCK抑制剂TL4-12可剂量依赖性地下调IKZF1和BCL-6的表达,抑制MM细胞增殖并诱导其凋亡。

总而言之,该研究数据确定GCK是RASMut MM细胞中的一个新靶点,为治疗MM中的RAS突变提供了理论基础。此外,GCK抑制剂可能是克服MM中IMiD耐药的一种替代疗法。

原始出处:

Shirong Li, et al. Targeting GCK pathway: a novel and selective therapeutic strategy against RAS mutated multiple myeloma. Blood. October 09, 2020.

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    2024-05-23 jshbyywk2008 来自北京

    靶向MM中的RAS突变将提高治疗效率,并有可能克服耐药性。

    0

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    2020-10-13 bioon7
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    2020-10-11 1209e435m98(暂无昵称)

    学习了,谢谢分享

    0

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