Synergistic antitumor activity of regorafenib and lapatinib in preclinical models of human colorectal cancer

Wen-Ji Zhang; Yong Li; Meng-Ning Wei; Yao Chen; Jian-Ge Qiu; Qi-Wei Jiang; Yang Yang; Di-Wei Zheng; Wu-Ming Qin; Jia-Rong Huang; Kun Wang; Wen-Juan Zhang; Yi-Jun Wang; Dong-Hua Yang; Zhe-Sheng Chen; Zhi Shi

doi:10.1016/j.canlet.2016.11.011

Synergistic antitumor activity of regorafenib and lapatinib in preclinical models of human colorectal cancer

Cancer Lett. 2017 Feb 1:386:100-109. doi: 10.1016/j.canlet.2016.11.011. Epub 2016 Nov 15.

Authors

Wen-Ji Zhang¹, Yong Li², Meng-Ning Wei¹, Yao Chen¹, Jian-Ge Qiu¹, Qi-Wei Jiang¹, Yang Yang¹, Di-Wei Zheng¹, Wu-Ming Qin¹, Jia-Rong Huang¹, Kun Wang¹, Wen-Juan Zhang³, Yi-Jun Wang⁴, Dong-Hua Yang⁴, Zhe-Sheng Chen⁵, Zhi Shi⁶

Affiliations

¹ Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China.
² Department of Gastrointestinal Surgery & General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China.
³ Department of Preventive Medicine, College of Medicine, Jinan University, Guangzhou, Guangdong 510632, China.
⁴ Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
⁵ Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, PR China. Electronic address: chenz@stjohns.edu.
⁶ Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China. Electronic address: tshizhi@jnu.edu.cn.

PMID: 27864115
DOI: 10.1016/j.canlet.2016.11.011

Abstract

Regorafenib significantly prolongs overall survival in patients with metastatic colorectal cancer (mCRC), but the overall clinical efficacy of regorafenib remains quite limited. Combination chemotherapy is a potentially promising approach to enhance anticancer activity, overcome drug resistance, and improve disease-free and overall survival. The current study investigates the antitumor activity of regorafenib in combination with lapatinib in preclinical models of human CRC. Our results show improved antitumor efficacy when regorafenib is combined with lapatinib both in vitro and in vivo. Furthermore, pharmacokinetic analyses revealed that regorafenib and lapatinib do not influence on each plasma concentration. The finding that regorafenib in combination with lapatinib have synergistic activity warrants further clinical investigation of this beneficial combination as a potential treatment strategy for CRC patients.

Keywords: Colorectal cancer; Combination chemotherapy; Lapatinib; Regorafenib; Targeted therapy.

MeSH terms

Angiogenesis Inhibitors / pharmacokinetics
Angiogenesis Inhibitors / pharmacology*
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Cell Cycle Checkpoints / drug effects
Cell Proliferation / drug effects
Colorectal Neoplasms / blood
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / pathology
Dose-Response Relationship, Drug
Drug Synergism
Female
HCT116 Cells
HT29 Cells
Humans
Inhibitory Concentration 50
Lapatinib
Mice, Inbred BALB C
Mice, Nude
Molecular Targeted Therapy
Neovascularization, Pathologic
Phenylurea Compounds / pharmacokinetics
Phenylurea Compounds / pharmacology*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Pyridines / pharmacokinetics
Pyridines / pharmacology*
Quinazolines / pharmacokinetics
Quinazolines / pharmacology*
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

Angiogenesis Inhibitors
Phenylurea Compounds
Protein Kinase Inhibitors
Pyridines
Quinazolines
Lapatinib
regorafenib