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

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.

• Authors: Chongchong Tian, Pingping Ding, Ziqiao Yuan, Han Li, Yanxia Zhao, Lan Sun, Qingming Guo, Zhenzhong Wang, Lixin Sun, Luyong Zhang, Zhenzhou Jiang
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 20 Issue 12 Pg. 1599-612 (Dec 2015) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 26437915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Quinazolines
• Lapatinib
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy)
• Cell Cycle Checkpoints (drug effects)
• Cell Line
• Cell Line, Tumor
• ErbB Receptors (antagonists & inhibitors)
• G1 Phase (drug effects)
• Humans
• Lapatinib
• Protein Kinase Inhibitors (pharmacology)
• Quinazolines (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors)
• Resting Phase, Cell Cycle (drug effects)
• Signal Transduction (drug effects)
• Stomach Neoplasms (drug therapy)