Mammalian target of rapamycin inhibition in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin (mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase III studies, mTORC1 inhibitors demonstrate anti-tumor activity in advanced HCC, but dual mTOR (mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.

Keywords: Mammalian target of rapamycin, hepatocellular carcinoma, Mammalian target of rapamycin complex 1, Mammalian target of rapamycin complex 2, PI3K/AKT/mTOR signaling pathway, Sorafenib, Everolimus, Sirolimus, Liver transplantation, CC-223

Core tip: Advanced hepatocellular carcinoma (HCC) has a poor prognosis with limited therapeutic options. The mammalian target of rapamycin (mTOR) pathway (regulated by mTORC1 and mTORC2) is implicated in HCC pathogenesis. This review examines pre-clinical and clinical data demonstrating that mTORC1 inhibition effectively prevents HCC recurrence post-liver transplantation, and also has a modest anti-tumor effect in advanced HCC. The rationale and preclinical data for utilizing dual mTOR (mTORC1 and mTORC2) inhibition in HCC is also reviewed; a current phase I clinical trial to investigate the efficacy of dual mTOR inhibitors is briefly discussed. mTOR pathway inhibition has therapeutic potential in the treatment of advanced HCC.