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...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.展开更多
基金supported by grants from the National Key Project for Infectious Disease of China(No.2017ZX 10203207)and the National Natural Science Foundation of China(Nos.81972737.81930074,91959203,and 81872356).
文摘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.
