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

  • Apoptosis. 2015 Dec;20(12):1599-612. doi: 10.1007/s10495-015-1164-7.
Chongchong Tian  1 ,  Pingping Ding  1 ,  Ziqiao Yuan  1 ,  Han Li  1 ,  Yanxia Zhao  1 ,  Lan Sun  2  3 ,  Qingming Guo  2  3 ,  Zhenzhong Wang  2  3 ,  Lixin Sun  1  4 ,  Luyong Zhang  5  6  7 ,  Zhenzhou Jiang  8  9  10
Affiliations
  • 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. [email protected].
  • 6. Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing, 210009, China. [email protected].
  • 7. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. [email protected].
  • 8. Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China. [email protected].
  • 9. Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China. [email protected].
  • 10. Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China. [email protected].
PMID: 26437915 DOI: 10.1007/s10495-015-1164-7
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.
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