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当代肿瘤药物靶点

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

GDC-0980在小儿白血病中抑制PI3K / mTOR途径：对异常FLT-3活性的影响以及与细胞内信号传导靶标的合作

卷 19, 期 10, 2019

页: [828 - 837] 页: 10

弟呕挨: 10.2174/1568009619666190326120833

价格: $65

摘要

背景：GDC-0980是I类PI3K和mTOR途径的选择性小分子抑制剂，具有有效的抗增殖活性。 目的：我们着手评估GDC-0980在临床前研究中对儿童白血病细胞的疗效。 方法：使用五种不同的小儿白血病细胞体外评估GDC-0980的抗肿瘤活性。 结果：我们的数据显示，GDC-0980显着抑制白血病细胞系KOPN8（IC50，532 nM），SEM（IC50,720 nM），MOLM-13（IC50,346 nM），MV4; 11（IC50， 199 nM）和TIB-202（IC50，848 nM），与正常对照细胞（1.23μM）相比。这种抗增殖活性与细胞凋亡机制的激活有关，其特征在于Bcl-2蛋白磷酸化的减少和PARP裂解的增强。 GDC-0980处理的细胞的蛋白质印迹分析还显示mTOR，Akt和S6的磷酸化水平降低，但ERK1 / 2却没有。值得注意的是，应用GDC-0980后，Molm-13和MV4; 11细胞中的FLT3磷酸化降低。我们进一步检查了从小儿白血病患者分离得到的GDC-0980治疗的原发性白血病细胞的细胞活力。这项研究揭示了GDC-0980对两名ALL患者的潜在治疗作用（分别为IC50、1.23和0.625μM）。 GDC-0980的药物组合分析显示与MEK抑制剂Cobimetinib（MV4-11; 11，CI，0.25，SEM，CI，0.32和TIB-202，CI，0.55）和靶向FLT3抑制剂Crenolanib（ MV4-11； 11，CI，0.25，SEM，CI，0.7，和TIB-202，CI，0.42）。 结论：这些发现为初步的概念验证数据和进一步研究小儿白血病患者亚组中GDC-0980的依据提供了依据。

关键词: FLT3，PI3K，mTOR，细胞毒性，ITD，ALL，AML。

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