PMID- 34669157
OWN - NLM
STAT- MEDLINE
DCOM- 20220722
LR  - 20220725
IS  - 2095-0225 (Electronic)
IS  - 2095-0217 (Linking)
VI  - 16
IP  - 3
DP  - 2022 Jun
TI  - Rapamycin enhances the anti-tumor activity of cabozantinib in cMet 
      inhibitor-resistant hepatocellular carcinoma.
PG  - 467-482
LID - 10.1007/s11684-021-0869-y [doi]
AB  - 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.
CI  - (c) 2021. Higher Education Press.
FAU - Gao, Chao
AU  - Gao C
AD  - Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, 
      Fudan University, Shanghai, 200040, China.
FAU - Wang, Shenghao
AU  - Wang S
AD  - Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, 
      Fudan University, Shanghai, 200040, China.
FAU - Shao, Weiqing
AU  - Shao W
AD  - Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, 
      Fudan University, Shanghai, 200040, China.
FAU - Zhang, Yu
AU  - Zhang Y
AD  - Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, 
      Fudan University, Shanghai, 200040, China.
FAU - Lu, Lu
AU  - Lu L
AD  - Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, 
      Fudan University, Shanghai, 200040, China.
FAU - Jia, Huliang
AU  - Jia H
AD  - Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, 
      Fudan University, Shanghai, 200040, China.
FAU - Zhu, Kejin
AU  - Zhu K
AD  - Kanion Research Institute, Lianyungang, 222002, China.
FAU - Chen, Jinhong
AU  - Chen J
AD  - Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, 
      Fudan University, Shanghai, 200040, China.
FAU - Dong, Qiongzhu
AU  - Dong Q
AD  - Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, 
      Fudan University, Shanghai, 200040, China.
AD  - Institutes of Biomedical Sciences, Fudan University, Shanghai, 200040, China.
FAU - Lu, Ming
AU  - Lu M
AD  - Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, 
      Fudan University, Shanghai, 200040, China.
FAU - Zhu, Wenwei
AU  - Zhu W
AD  - Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, 
      Fudan University, Shanghai, 200040, China. westoolife@163.com.
FAU - Qin, Lunxiu
AU  - Qin L
AD  - Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, 
      Fudan University, Shanghai, 200040, China. qinlx@fudan.edu.cn.
AD  - Institutes of Biomedical Sciences, Fudan University, Shanghai, 200040, China. 
      qinlx@fudan.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20211020
PL  - China
TA  - Front Med
JT  - Frontiers of medicine
JID - 101549428
RN  - 0 (Anilides)
RN  - 0 (Pyridines)
RN  - 1C39JW444G (cabozantinib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - *Anilides/pharmacology
MH  - Animals
MH  - *Carcinoma, Hepatocellular/drug therapy
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Endothelial Cells/metabolism
MH  - Humans
MH  - *Liver Neoplasms/drug therapy
MH  - *Pyridines/pharmacology
MH  - *Sirolimus/pharmacology
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - cabozantinib
OT  - hepatocellular carcinoma
OT  - primary resistance
OT  - rapamycin
EDAT- 2021/10/21 06:00
MHDA- 2022/07/23 06:00
CRDT- 2021/10/20 12:33
PHST- 2020/12/15 00:00 [received]
PHST- 2021/05/28 00:00 [accepted]
PHST- 2021/10/21 06:00 [pubmed]
PHST- 2022/07/23 06:00 [medline]
PHST- 2021/10/20 12:33 [entrez]
AID - 10.1007/s11684-021-0869-y [pii]
AID - 10.1007/s11684-021-0869-y [doi]
PST - ppublish
SO  - Front Med. 2022 Jun;16(3):467-482. doi: 10.1007/s11684-021-0869-y. Epub 2021 Oct 
      20.