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Apoptosis. 2015 Dec;20(12):1599-612. doi: 10.1007/s10495-015-1164-7.

A novel dual EGFR/HER2 inhibitor KU004 induces cell cycle arrest and apoptosis in HER2-overexpressing cancer cells.

Tian C1, Ding P1, Yuan Z1, Li H1, Zhao Y1, Sun L2,3, Guo Q2,3, Wang Z2,3, Sun L1,4, Zhang L5,6,7, Jiang Z8,9,10.

Author information

1
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
2
Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, 222001, Jiangsu, China.
3
State Key Laboratory of Pharmaceutical Process New-tech for Chinese Medicine, Lianyungang, 222001, Jiangsu, China.
4
Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing, 210009, China.
5
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China. lyzhang@cpu.edu.cn.
6
Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing, 210009, China. lyzhang@cpu.edu.cn.
7
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. lyzhang@cpu.edu.cn.
8
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China. beaglejiang@cpu.edu.cn.
9
Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China. beaglejiang@cpu.edu.cn.
10
Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China. beaglejiang@cpu.edu.cn.

Abstract

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

PMID:
26437915
DOI:
10.1007/s10495-015-1164-7
[Indexed for MEDLINE]

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