title: 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.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Chongchong
authors.initials: C
authors.lastname: Tian
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Ding
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Ziqiao
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Han
authors.initials: H
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, 222001, Jiangsu, China.|State Key Laboratory of Pharmaceutical Process New-tech for Chinese Medicine, Lianyungang, 222001, Jiangsu, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Sun
authors.affiliation: Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, 222001, Jiangsu, China.|State Key Laboratory of Pharmaceutical Process New-tech for Chinese Medicine, Lianyungang, 222001, Jiangsu, China.
authors.forename: Qingming
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, 222001, Jiangsu, China.|State Key Laboratory of Pharmaceutical Process New-tech for Chinese Medicine, Lianyungang, 222001, Jiangsu, China.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.|Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing, 210009, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China. lyzhang@cpu.edu.cn.|Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing, 210009, China. lyzhang@cpu.edu.cn.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. lyzhang@cpu.edu.cn.
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China. beaglejiang@cpu.edu.cn.|Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China. beaglejiang@cpu.edu.cn.|Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China. beaglejiang@cpu.edu.cn.
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: Apoptosis; Cell cycle arrest; HER2; KU004