BENC-511, a novel PI3K inhibitor, suppresses metastasis of non-small cell lung cancer cells by modulating β-catenin/ZEB1 regulatory loop.

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.