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 PI3Kα/δ 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].

中文翻译：

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通过ERBB3 / PI3K增强的信号传导在暴露于[neratinib + valproate]的胰腺肿瘤细胞中起着补偿性生存的作用。

ERBB1 / 2/4抑制剂neratinib导致质膜相关的K-RAS错位进入细胞内囊泡；HDAC抑制剂可增强这种效果，[奈拉替尼+丙戊酸钠]的组合现已成为一项I期试验（NCT03919292）。进行本研究是为了了解在[neratinib + valproate]暴露后发生的耐药机制。胰腺肿瘤细胞暴露于[neratinib +丙戊酸钠]最初会降低ERBB家族受体c-MET和c-KIT的表达和磷酸化。经过24小时的药物暴露和在无药物条件下进一步培养24小时后，对c-MET，c-KIT和大多数ERBB家族受体的影响已恢复到接近基线水平。但是，ERBB3的表达和磷酸化增加，这与AKT T308磷酸化升高有关。敲低ERBB3可以显着增强[neratinib +丙戊酸酯]的杀伤力，这与AKT，mTOR，p70 S6K和ERK1 / 2的更大失活有关。PI3Kα/δ抑制剂copanlisib也显着增强了[neratinib + valproate]暴露后的杀伤力。通过自动吞噬体的形成和自噬通量，帕潘西布提高了[奈拉替尼+丙戊酸酯]的杀伤力。我们的数据证明了可将帕潘替尼与[奈拉替尼+丙戊酸酯]安全合并使用的进一步体内探索。