J Clin Invest. 2014 May;124(5):2037-49. doi: 10.1172/JCI72522. Epub 2014 Apr 8.
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 EPHA2 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.
全基因组分析先前确定，受体酪氨酸激酶 (RTK) EPHA2 在非小细胞肺癌 (NSCLC) 中普遍过表达。EPHA2 过表达与不良临床结局相关；因此，EPHA2 可能代表 NSCLC 患者有希望的治疗靶点。支持这一假说，我们在此表明，在侵袭性 Kras 突变型 NSCLC 的小鼠模型中靶向破坏 EphA2 会损害肿瘤生长。在人 NSCLC 细胞系中敲低 EPHA2 可降低细胞生长和活力，证实了 EphA2 在 NSCLC 中上皮细胞自主的需求。在 NSCLC 中靶向 EPHA2 可降低 S6K1 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 EphA2 敲低可减少肿瘤体积并诱导肿瘤细胞死亡。此外，一种 ATP 竞争性 EphA2 RTK 抑制剂 ALW-II-41-27 在体外以时间和剂量依赖性方式减少了 NSCLC 细胞的存活数量，并在体内诱导了人 NSCLC 异种移植物的肿瘤消退。总的来说，这些数据表明 EPHA2 在 NSCLC 的维持和进展中起作用，并提供了证据表明 ALW-II-41-27 可有效抑制 EphA2 介导的 NSCLC 临床前模型中的肿瘤生长。
