The Role of mTOR in Neuroendocrine Tumors: Future Cornerstone of a Winning Strategy?

Abstract

The mechanistic target of rapamycin (mTOR) is part of the phosphoinositide-3-kinase (PI3K)/protein kinase B (AkT)/mTOR pathway and owes its name to the inhibitory effect of rapamycin. The mTOR has a central converging role for many cell functions, serving as a sensor for extracellular signals from energy status and nutrients availability, growth factors, oxygen and stress. Thus, it also modulates switch to anabolic processes (protein and lipid synthesis) and autophagy, in order to regulate cell growth and proliferation. Given its functions in the cell, its deregulation is implicated in many human diseases, including cancer. Its predominant role in tumorigenesis and progression of neuroendocrine tumors (NETs), in particular, has been demonstrated in preclinical studies and late clinical trials. mTOR inhibition by everolimus is an established therapeutic target in NETs, but there are no identified predictive or prognostic factors. This review is focused on the role of mTOR and everolimus in NETs, from preclinical studies to major clinical trials, and future perspectives involving mTOR in the treatment of NETs.

Keywords: Akt; PTEN; RAD001; RADIANT; carcinoid; everolimus; mTOR; mTORC1; neuroendocrine tumor; neuroendocrine tumors.

Figure 1

Schematic representation of the phosphoinositide-3-kinase (PI3K)/protein kinase B (AkT)/ mechanistic target of rapamycin (mTOR) pathway. Black arrow: direct activation; Dotted black arrow: activation through unknown/not diasplayed other molecules; Dotted T bar: inhibition; Black/red twisting arrows: activation/inactivation conversion; Red arrow: promotion of processes; Red T bar: inhibition of processes; P in yellow spheres: phosphate group.