Dramatic antitumor effects of the dual mTORC1 and mTORC2 inhibitor AZD2014 in hepatocellular carcinoma

摘要

The mammalian target of rapamycin (mTOR) has emerged as a critical effector in cell growth, proliferation, survival, angiogenesis, and autophagy through direct interaction with mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2). The mTOR axis is aberrantly activated in about 50% of human hepatocellular carcinoma (HCC) cases and thus has become an attractive target for drug development in this disease. Allosteric inhibitors of mTORC1, rapamycin and its derivatives have been used to study in patients with HCC but have not shown significant clinical utility, likely because of the lack of inhibition of mTORC2. In the present study, we describe that AZD2014, a small molecular ATP-competitive inhibitor of mTOR, was a highly potent inhibitor of mTORC1 and mTORC2 in human HCC cells, which led to a more thorough inhibition of mTORC1 than rapamycin, and the inhibition of mTORC2 prevented the feedback activation of AKT signaling. Compared with rapamycin, AZD2014 resulted in more profound proliferation suppression, apoptosis, cell cycle arrest, and autophagy in HCC cells. Notably, we found blockage of both mTORC1 and mTORC2 by AZD2014 to be more efficacious than blockage of mTORC1 alone by rapamycin in inhibiting the migration, invasion and EMT progression of HCC cells. In conclusion, our current results highlight mechanistic differentiation between rapamycin and AZD2014 in targeting cancer cell proliferation, cell cycle, apoptosis, autophagy, migration, invasion and EMT progression, and provide support for further investigation of AZD2014 as an antitumor agent for the treatment of HCC in clinic.