Rapamycin enhances the anti-tumor activity of cabozantinib in cMet inhibitor-resistant hepatocellular carcinoma.
10.1007/s11684-021-0869-y
- Author:
Chao GAO
1
;
Shenghao WANG
1
;
Weiqing SHAO
1
;
Yu ZHANG
1
;
Lu LU
1
;
Huliang JIA
1
;
Kejin ZHU
2
;
Jinhong CHEN
1
;
Qiongzhu DONG
1
;
Ming LU
1
;
Wenwei ZHU
3
;
Lunxiu QIN
4
Author Information
1. Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, 200040, China.
2. Kanion Research Institute, Lianyungang, 222002, China.
3. Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, 200040, China. westoolife@163.com.
4. Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, 200040, China. qinlx@fudan.edu.cn.
- Publication Type:Journal Article
- Keywords:
cabozantinib;
hepatocellular carcinoma;
primary resistance;
rapamycin
- MeSH:
Anilides/pharmacology*;
Animals;
Carcinoma, Hepatocellular/drug therapy*;
Cell Line, Tumor;
Cell Proliferation;
Endothelial Cells/metabolism*;
Humans;
Liver Neoplasms/drug therapy*;
Pyridines/pharmacology*;
Sirolimus/pharmacology*;
Xenograft Model Antitumor Assays
- From:
Frontiers of Medicine
2022;16(3):467-482
- CountryChina
- Language:English
-
Abstract:
Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.
