Inhibition of glycolysis by a novel EGFR/HER2 inhibitor KU004 suppresses the growth of HER2+ cancer

Chongchong Tian; Ziqiao Yuan; Dengqiu Xu; Pingping Ding; Tao Wang; Luyong Zhang; Zhenzhou Jiang

doi:10.1016/j.yexcr.2017.05.019

Inhibition of glycolysis by a novel EGFR/HER2 inhibitor KU004 suppresses the growth of HER2+ cancer

Exp Cell Res. 2017 Aug 15;357(2):211-221. doi: 10.1016/j.yexcr.2017.05.019. Epub 2017 May 19.

Authors

Chongchong Tian¹, Ziqiao Yuan¹, Dengqiu Xu¹, Pingping Ding¹, Tao Wang², Luyong Zhang³, Zhenzhou Jiang⁴

Affiliations

¹ Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
² 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.
³ 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; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: lyzhang@cpu.edu.cn.
⁴ Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China. Electronic address: beaglejiang@cpu.edu.cn.

PMID: 28532652
DOI: 10.1016/j.yexcr.2017.05.019

Abstract

Upregulation of glycolysis was often observed in human HER2-overexpressing cancers. In this study, we demonstrated that KU004, a dual novel EGFR/HER2 inhibitor, disrupted cancer cell proliferation via modulation of glycolysis. KU004, inhibited the Warburg effect by suppressing hexokinase II (HK2) expression at the transcriptional and post-translational levels. Further study demonstrated that the downregulation of HKII by KU004 was mainly mediated by the PI3K/Akt signaling pathway. Furthermore, the role of HKII downregulation in KU004-mediated antitumor effect was also confirmed in our in vivo xenograft model. Collectively, these data suggest that multifaceted targeting the aberrant glucose metabolism along with the upstream HER2 may be an effective approach for clinical treatment against HER2+ cancer.

Keywords: Glycolysis; HER2; Hexokinase II; KU004.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclic P-Oxides / pharmacology*
Glycolysis / drug effects
Humans
Phosphatidylinositol 3-Kinases / metabolism
Quinazolines / pharmacology*
Receptor, ErbB-2 / metabolism*
Signal Transduction / drug effects

Substances

Antineoplastic Agents
Cyclic P-Oxides
KU004 compound
Quinazolines
Phosphatidylinositol 3-Kinases
ERBB2 protein, human
Receptor, ErbB-2