Role of the mTOR pathway in liver cancer: from molecular genetics to targeted therapies.

: Primary liver cancers, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), are highly lethal and frequent tumors worldwide, with few effective treatment options. The mammalian target of Rapamycin (mTOR) complex is a central regulator of cell growth and metabolism by its ability to integrate inputs from amino acids, nutrients and extracellular signals. The mTOR protein is incorporated into two distinct complexes: mammalian target of Rapamycin complex 1 (mTORC1) and mammalian target of Rapamycin complex 2 (mTORC2). Specifically, mTORC1 regulates protein synthesis, glucose and lipid metabolism, and autophagy, whereas mTORC2 promotes liver tumorigenesis via modulating the AGC family of serine/threonine kinases, especially the AKT (protein kinase B) proteins. In human HCC and iCCA samples, genomics analyses have unraveled the frequent de-regulation of the mTOR complexes. Both in vitro and in vivo studies have demonstrated the key role of mTORC1 and mTORC2 in liver tumor development and progression. The first generation mTOR inhibitors have been evaluated for effectiveness in liver tumor treatment and provided unsatisfactory results. Current research efforts are devoted to generating more efficacious mTOR inhibitors and identify biomarkers for patient selection as well as for novel combination therapies. Here, we provide a comprehensive review of the mechanisms leading to deregulated mTOR signaling cascade in liver cancers, the mechanisms whereby the mTOR pathway contributes to HCC and iCCA molecular pathogenesis, the therapeutic strategies, and the challenges that we need to overcome to effectively inhibit mTOR in liver cancer treatment. In conclusion: Deregulated mTOR signaling significantly contributes to HCC and iCCA molecular pathogenesis. mTOR inhibitors, presumably administered in association with other drugs, might be effective against subsets of human liver tumors.