Table 2.

Summary of the main experimental findings of the AKT/mTOR inhibitors

Durgs	Mechanisms of action	Preclinical findings	Clinical Trials	Reference
AKT inhibitors
MK2206	Allosteric pan-AKT inhibitor	MK2206 inhibited HCC cellular proliferation via induction of apoptosis and cell cycle arrest. MK2206 and capmatinib (c-Met inhibitor) additively or synergistically suppressed sorafenib-resistant HCC cells in vitro and sorafenib-resistant HCC xenografts in mice. Treatment with the MK-2206 repressed liver tumorigenesis in Pten−/− Sav1−/− mice, suggesting crosstalk between AKT and YAP/TAZ through IRS2.	NCT01239355	[106-108]
GDC-0068	ATP competitive pan-AKT inhibitor	GDC0068 promoted cell apoptosis in HCC cells. GDC0068 synergized with sorafenib to suppress the growth of sorafenib-resistant HCC tumors in vivo.	NCT02465060	[109, 110]
ARQ 751	Allosteric pan-AKT inhibitor	ARQ751 showed an anti-tumor effect in a DEN-induced cirrhotic rat model of HCC by increasing apoptosis and decreasing proliferation in the tumors.	NCT02761694 1	[111]
ARQ 092	Allosteric pan-AKT inhibitor	ARQ092 showed an anti-neoplastic effect in a DEN-induced cirrhotic rat model of HCC by inducing apoptosis and decreasing proliferation in the tumors.	N/A	[112]
mTOR inhibitors
Rapalogs	Rapamycin analogs 2	Oral administration of RAD001 (everolimus) to mice HCC PDXs resulted in a dose-dependent tumor growth inhibition. RAD001-induced growth suppression was associated with the inactivation of mTOR downstream targets, reduction in VEGF expression and microvessel density, inhibition of cell proliferation, and downregulation of the cell cycle genes.		[113]
MLN0128	Pan-mTOR inhibitor	MLN0128 effectively inhibited both mTORC1 and mTORC2, leading to the suppression of cell growth and induction of apoptosis in vitro and in vivo.	NCT02575339	[114]
CC-233	Pan-mTOR inhibitor	CC-233 exhibited significant cytotoxicity and growth suppression potency against HCC cell lines and primary human HCC cells. Furthermore, CC-223 oral administration dramatically inhibited HepG2 xenograft growth.	NCT01177397	[115]
NVP-BEZ235	Dual PI3K/mTOR inhibitor	NVP-BEZ235 reverted the metabolic abnormalities and cell growth driven by the insulin signaling pathway in a rat model of insulin-induced hepatocarcinogenesis.	N/A	[116]

^1.ARQ 751 is under clinical trials among solid tumor patients with PIK3CA/AKT/PTEN mutations.

^2.Due to the limited efficacy of Rapalogs as monotherapy against HCC, multiple clinical trials have been conducted or are ongoing to evaluate the therapeutic efficacy of Rapalogs in combination therapies. Abbreviation: N/A, not applicable.