a Department of Biochemistry and Molecular Biology , Virginia Commonwealth University , Richmond , VA , USA.
b Department of Medicine , Virginia Commonwealth University , Richmond , VA , USA.
Cancer Biol Ther. 2018 Feb 1;19(2):132-137. doi: 10.1080/15384047.2017.1394556. Epub 2017 Dec 8.
The FDA approved irreversible inhibitor of ERBB1/2/4, neratinib, was recently shown to rapidly down-regulate the expression of ERBB1/2/4 as well as the levels of c-MET and mutant K-RAS via autophagic degradation. In the present studies, in a dose-dependent fashion, neratinib reduced the expression levels of mutant K-RAS or of mutant N-RAS, which was augmented in an additive to greater than additive fashion by the HDAC inhibitors sodium valproate and AR42. Neratinib could reduce PDGFRα levels in GBM cells, that was enhanced by sodium valproate. Knock down of Beclin1 or of ATG5 prevented neratinib and neratinib combined with sodium valproate / AR42 from reducing the expression of mutant N-RAS in established PDX and fresh PDX models of ovarian cancer and melanoma, respectively. Neratinib and the drug combinations caused the co-localization of mutant RAS proteins and ERBB2 with Beclin1 and cathepsin B. The drug combination activated the AMP-dependent protein kinase that was causal in enhancing HMG Co A reductase phosphorylation. Collectively, our data reinforce the concept that the irreversible ERBB1/2/4 inhibitor neratinib has the potential for use in the treatment of tumors expressing mutant RAS proteins.
美国食品和药物管理局批准的 ERBB1/2/4 不可逆抑制剂奈拉替尼，最近被证明能够通过自噬降解快速下调 ERBB1/2/4 以及 c-MET 和突变型 K-RAS 的水平。在本研究中，奈拉替尼以剂量依赖的方式降低了突变型 K-RAS 或突变型 N-RAS 的表达水平，而组蛋白去乙酰化酶抑制剂丙戊酸钠和 AR42 则以附加的方式增强了这种作用，使其大于附加作用。奈拉替尼可以降低 GBM 细胞中 PDGFRα 的水平，而丙戊酸钠可以增强这种作用。Beclin1 或 ATG5 的敲低可以阻止奈拉替尼和奈拉替尼联合丙戊酸钠/AR42 降低卵巢癌和黑色素瘤的 PDX 和新鲜 PDX 模型中突变型 N-RAS 的表达。奈拉替尼和药物组合导致突变型 RAS 蛋白和 ERBB2 与 Beclin1 和组织蛋白酶 B 共定位。该药物组合激活了 AMP 依赖性蛋白激酶，该激酶在增强 HMG Co A 还原酶磷酸化中起因果作用。总之，我们的数据强化了这样一个概念，即不可逆的 ERBB1/2/4 抑制剂奈拉替尼有可能用于治疗表达突变型 RAS 蛋白的肿瘤。
