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首页> 外文期刊>Cellular Signalling >Enhanced signaling via ERBB3/PI3K plays a compensatory survival role in pancreatic tumor cells exposed to [neratinib plus valproate]
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Enhanced signaling via ERBB3/PI3K plays a compensatory survival role in pancreatic tumor cells exposed to [neratinib plus valproate]

机译:通过ERBB3 / PI3K增强的信号传导在暴露于[Neratinib Plus Valproate]的胰腺肿瘤细胞中起补偿存活作用

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The ERBB1/2/4 inhibitor neratinib causes plasma membrane-associated K-RAS to mislocalize into intracellular vesicles; this effect is enhanced by HDAC inhibitors and the combination of [neratinib + sodium valproate] is now a phase I trial (NCT03919292). The present studies were performed to understand resistance mechanisms that evolve following [neratinib + valproate] exposure. Exposure of pancreatic tumor cells to [neratinib + sodium valproate] initially reduced the expression and phosphorylation of ERBB family receptors, c-MET and c-KIT. Following a 24 h drug exposure and a further 24 h culture in drug free conditions, the effects on c-MET, c-KIT and most ERBB family receptors had returned to near baseline levels. However, the expression and phosphorylation of ERBB3 were increased which was associated with elevated AKT T308 phosphorylation. Knock down of ERBB3 significantly enhanced [neratinib + valproate] lethality, which was associated with greater inactivation of AKT, mTOR, p70 S6K and ERK1/2. The PI3K alpha/delta inhibitor copanlisib also significantly enhanced killing after [neratinib + valproate] exposure. Copanlisib enhanced [neratinib + valproate] lethality via autophagosome formation and autophagic flux. Our data argue for further in vivo exploration as to whether copanlisib can be safely combined with [neratinib + valproate].
机译:ERBB1 / 2/4抑制剂内替尼使血浆膜相关的K-RA在细胞内囊泡中均匀化; HDAC抑制剂增强了这种效果,[Neratinib +钠丙戊酸]的组合现在是I期试验(NCT03919292)。进行本研究以了解抗性抗性机制,其在[南替尼+戊酸酯]暴露之后。胰腺肿瘤细胞暴露于[neratinib +戊酸钠]最初降低了ERBB家族受体,C-Met和C-kit的表达和磷酸化。在药物无毒条件下24小时药物暴露和另外24小时培养后,对C-Met,C-kit和大多数ERBB家族受体的影响返回到附近的基线水平。然而,增加了ERBB3的表达和磷酸化,其与升高的AKT T308磷酸化相关。击倒erbb3显着增强了[Neratinib + Valproate]致死性,其与AKT,MTOR,P70 S6K和ERK1 / 2的更大灭活相关。 PI3Kα/ Delta抑制剂Copanlisib在[Neratinib + Valproate]暴露后也显着提高了杀戮。 Copanlisib通过自噬体形成和自噬助焊剂增强了[Neratinib + Valproate]致死性。我们的数据进一步探讨了柯南斯利布是否可以安全地与[Neratinib + Valproate]安全地探讨。

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