Non-small cell lung cancer (NSCLC) is known as highly metastatic disease because it is difficult to diagnose at early stage. More than 60% of NSCLC patients' overexpress receptor tyrosine kinase (RTK) such as EGFR that has been proved to display resistance to receptor tyrosine kinase inhibitor (TKI) through PI3K signaling, while single PI3K inhibitors increase RTK expression as feedback. So, to select the proper targeted agent or target an assortment of molecular subsets, such as EGFR mutations for different subgroups of patients with NSCLC is urgent. Compound BENC-511, a potent PI3K inhibitor, had effects on inhibiting cancer cell survival and delaying tumor growth, but the effects and mechanisms on cancer metastasis are not clear. Methods of Scratch assay, Transwell system, experimental metastasis mice models, plasmid transfection, quantitative real-time PCR and Western blot were used. Results showed that BENC-511 could significantly inhibit lung cancer cells invasion and metastasis both in vitro and in vivo. And it not only inhibited PI3K/Akt signal pathway, but also directly suppressed phosphorylation of EGFR and nuclear translocation of β-catenin. Moreover, our study firstly reported BENC-511 seemed more sensitive to NSCLC cells that highly expressed Zinc-finger E-box binding protein 1 (ZEB1), one of the epithelial-mesenchymal transition (EMT) inducer, and knockdown of ZEB1 could improve the effects of this compound. These findings suggested that BENC-511 should be a promising lead molecule for anti-metastasis therapy by targeting β-catenin/ZEB1 regulatory loop and serve as a therapeutic agent to inhibit metastasis of NSCLC.

非小细胞肺癌（NSCLC）被称为高度转移性疾病，因为它难以在早期诊断。超过60％的NSCLC患者的过表达受体酪氨酸激酶（RTK）（例如EGFR）已通过PI3K信号传导显示出对受体酪氨酸激酶抑制剂（TKI）的抗性，而单一PI3K抑制剂则通过反馈增加RTK表达。因此，为NSCLC患者的不同亚组选择合适的靶向药物或靶向各种分子亚类（例如EGFR突变）非常迫切。化合物BENC-511，一种有效的PI3K抑制剂，具有抑制癌细胞存活和延迟肿瘤生长的作用，但对癌症转移的作用和机制尚不清楚。Scratch分析方法，Transwell系统，实验性转移小鼠模型，质粒转染，使用定量实时PCR和Western印迹。结果显示BENC-511可以显着抑制肺癌细胞的侵袭和转移体外和体内。它不仅抑制PI3K / Akt信号通路，而且直接抑制EGFR的磷酸化和β-catenin的核易位。此外，我们的研究首次报道BENC-511似乎对高度表达锌指E-box结合蛋白1（ZEB1）（一种上皮-间质转化（EMT）诱导剂）的NSCLC细胞敏感，而敲低ZEB1可以改善这种情况。该化合物的作用。这些发现表明，BENC-511应该成为靶向β-catenin/ ZEB1调节环的抗转移治疗的有前途的先导分子，并作为抑制NSCLC转移的治疗剂。