Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC
Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC
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DOI：
10.1172/jci72522
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发表时间：
2014-05-01
影响因子：
15.9
通讯作者：
Chen, Jin
中科院分区：
文献类型：
--
作者：
Arnato, Katherine R.;Wang, Shan;Chen, Jin
全基因组分析先前确定受体酪氨酸激酶（RTK）EPHA 2通常在非小细胞肺癌（NSCLC）中过表达。EPHA 2过表达与不良临床结局相关;因此，EPHA 2可能代表NSCLC患者有希望的治疗靶点。为了支持这一假设，我们已经证明，在侵袭性Kras突变型NSCLC的鼠模型中靶向破坏EphA 2会损害肿瘤生长。人NSCLC细胞系中EPH 42的敲低降低了细胞生长和活力，证实了NSCLC中上皮细胞对EPHA 2的自主需求。靶向NSCLC中的EPHA 2降低了S6 K1介导的细胞死亡激动剂BAD的磷酸化并诱导细胞凋亡。在皮下小鼠模型中建立的NSCLC肿瘤内诱导EPHA 2敲低减少肿瘤体积并诱导肿瘤细胞死亡。此外，ATP竞争性EPHA 2 RTK抑制剂ALW-II-41-27以时间依赖性和剂量依赖性的方式减少了存活NSCLC细胞的数量。在体外以剂量依赖性方式诱导肿瘤消退，并在体内诱导人NSCLC异种移植物中的肿瘤消退。总的来说，这些数据证明了EPHA 2在NSCLC的维持和进展中的作用，并提供了ALW-II-41-27有效抑制NSCLC临床前模型中EPHA 2介导的肿瘤生长的证据。
Genome-wide analyses determined previously that the receptor tyrosine kinase (RTK) EPHA2 is commonly overexpressed in non-small cell lung cancers (NSCLCs). EPHA2 overexpression is associated with poor clinical outcomes; therefore, EPHA2 may represent a promising therapeutic target for patients with NSCLC. In support of this hypothesis, here we have shown that targeted disruption of EphA2 in a murine model of aggressive Kras-mutant NSCLC impairs tumor growth. Knockdown of EPH42 in human NSCLC cell lines reduced cell growth and viability, confirming the epithelial cell autonomous requirements for EPHA2 in NSCLCs. Targeting EPHA2 in NSCLCs decreased S6K1-mediated phosphorylation of cell death agonist BAD and induced apoptosis. Induction of EPHA2 knockdown within established NSCLC tumors in a subcutaneous murine model reduced tumor volume and induced tumor cell death. Furthermore, an ATP-competitive EPHA2 RTK inhibitor, ALW-II-41-27, reduced the number of viable NSCLC cells in a time-dependent and. dose-dependent manner in vitro and induced tumor regression in human NSCLC xenografts in vivo. Collectively, these data demonstrate a role for EPHA2 in the maintenance and progression of NSCLCs and provide evidence that ALW-II-41-27 effectively,inhibits EPHA2-mediated tumor growth in preclinical models of NSCLC.