HDAC inhibitors enhance neratinib activity and when combined enhance the actions of an anti-PD-1 immunomodulatory antibody in vivo.
HDAC inhibitors enhance neratinib activity and when combined enhance the actions of an anti-PD-1 immunomodulatory antibody in vivo.
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DOI：
10.18632/oncotarget.21660
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发表时间：
2017-10-27
期刊：
影响因子：
--
通讯作者：
Dent P
中科院分区：
文献类型：
--
作者：
Booth L;Roberts JL;Poklepovic A;Avogadri-Connors F;Cutler RE;Lalani AS;Dent P
NSCLC 肿瘤对阿法替尼产生耐药性的患者目前几乎没有有效的治疗选择来延长其生存期。阿法替尼耐药的 NSCLC 细胞对临床相关浓度的不可逆泛 HER 抑制剂来那替尼敏感，但对第一代 ERBB1/2/4 抑制剂拉帕替尼不敏感。在多个阿法替尼耐药的 NSCLC 克隆中，HDAC 抑制剂降低了 ERBB1/3/4 的表达，但激活了 c-SRC，从而导致 ERBB1/3 磷酸化总水平较高。 Neratinib 还迅速降低 ERBB1/2/3/4、c-MET 和突变型 K-/N-RAS 的表达； K-RAS 与磷酸化 ATG13 和组织蛋白酶 B 共定位于囊泡中。细胞联合暴露于[neratinib + HDAC抑制剂]导致mTORC1和mTORC2失活，增强自噬体和随后的自溶酶体形成，并导致细胞死亡的加和诱导大于加和诱导。 Beclin1 或 ATG5 的敲低可阻止 HDAC 抑制剂或 neratinib 降低 ERBB1/3/4 和 K-/N-RAS 表达，并降低 [neratinib + HDAC 抑制剂] 致死率。 Neratinib 和 HDAC 抑制剂通过自噬降低多种 HDAC 蛋白的表达，这导致 PD-L1、PD-L2 和鸟氨酸脱羧酶的表达减少，以及 I 类 MHCA 的表达增加。在体内，neratinib 和 HDAC 抑制剂相互作用，抑制 4T1 乳腺肿瘤的生长，抗 PD-1 抗体可以增强这种作用。我们的数据支持这样的前提：HDAC 抑制剂可以增强来那替尼的致死率，来那替尼可能是阿法替尼耐药 NSCLC 的有用治疗工具，并且[来那替尼 + HDAC 抑制剂]暴露可促进抗肿瘤免疫反应。
Patients whose NSCLC tumors become afatinib resistant presently have few effective therapeutic options to extend their survival. Afatinib resistant NSCLC cells were sensitive to clinically relevant concentrations of the irreversible pan-HER inhibitor neratinib, but not by the first generation ERBB1/2/4 inhibitor lapatinib. In multiple afatinib resistant NSCLC clones, HDAC inhibitors reduced the expression of ERBB1/3/4, but activated c-SRC, which resulted in higher total levels of ERBB1/3 phosphorylation. Neratinib also rapidly reduced the expression of ERBB1/2/3/4, c-MET and of mutant K-/N-RAS; K-RAS co-localized with phosphorylated ATG13 and with cathepsin B in vesicles. Combined exposure of cells to [neratinib + HDAC inhibitors] caused inactivation of mTORC1 and mTORC2, enhanced autophagosome and subsequently autolysosome formation, and caused an additive to greater than additive induction of cell death. Knock down of Beclin1 or ATG5 prevented HDAC inhibitors or neratinib from reducing ERBB1/3/4 and K-/N-RAS expression and reduced [neratinib + HDAC inhibitor] lethality. Neratinib and HDAC inhibitors reduced the expression of multiple HDAC proteins via autophagy that was causal in the reduced expression of PD-L1, PD-L2 and ornithine decarboxylase, and increased expression of Class I MHCA. In vivo, neratinib and HDAC inhibitors interacted to suppress the growth of 4T1 mammary tumors, an effect that was enhanced by an anti-PD-1 antibody. Our data support the premises that neratinib lethality can be enhanced by HDAC inhibitors, that neratinib may be a useful therapeutic tool in afatinib resistant NSCLC, and that [neratinib + HDAC inhibitor] exposure facilitates anti-tumor immune responses.
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影响因子：
--
作者：
Booth L;Roberts JL;Poklepovic A;Kirkwood J;Dent P
通讯作者：
Dent P
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作者：
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Dent P
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