Human epidermal growth factor receptor 2 (HER2) is a validated therapeutic target in cancer therapy, and HER2 protein-tyrosine kinase inhibitors have attracted considerable attention in the field of searching for novel anticancer drug candidates. In this study, we investigated the anticancer effect of KU004, a novel dual EGFR and HER2 inhibitor in vitro and in vivo. In vitro, KU004 preferentially inhibited the growth of HER2-overexpressing breast and gastric cell lines and HER2 expression level significantly correlated with response to KU004. It blocked activation of EGFR, HER2 and downstream Akt and Erk and induced G0/G1 arrest which was associated with downregulation of p53, p21, cyclin D1 and CDK4 along with increase of p27 and dephosphorylation of pRb. Apoptosis occurred in a caspase-dependent manner mainly via the extrinsic apoptotic pathway after KU004 treatment. The in vitro efficacy of KU004 was comparable to that of lapatinib. Moreover, KU004 suppressed the growth of NCI-N87 tumor and induced apoptosis without causing apparent weight loss or obvious toxicity. Tumor volume was significantly smaller in KU004-treated group than that in lapatinib-treated group at comparable dose levels. Taken together, these findings demonstrate KU004 can be expected to be a promising anti-HER2 candidate.
Keywords: Apoptosis; Cell cycle arrest; HER2; KU004.