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.

Two well-differentiated pancreatic neuroendocrine tumor mouse models

“…Additionally, an mTOR inhibitor, everolimus, is used to treat PanNET patients. Phosphatase and tensin homolog (PTEN), a key negative regulator of the PI3K/AKT/mTOR pathway, is frequently mutated or lost in several familial or sporadic cancer types; however, in PanNETs, the frequency of loss is low, 7-26.4% [21,[32][33][34][35][36][37][38]. Co-mutations of MEN1 and PTEN have been observed in a small percentage of human PanNETs [21,32].…”

False-positive findings on 6-[18F]fluor-l-3,4-dihydroxyphenylalanine PET (18F-FDOPA-PET) performed for imaging of neuroendocrine tumors

“…It has been suggested that upregulation of this transporter stimulates tumorigenesis by increasing the uptake of several amino acids, thereby enhancing protein synthesis. In addition, one of the major LAT substrates is leucine, which has been implicated in human carcinogenesis by activating mTORC 1 (mammalian target of rapamycin complex 1) (10,35,36,37,38). LAT-1 expression has been documented previously in various neoplasms such as squamous cell carcinomas, adenocarcinomas of the gastrointestinal tract, multiple myeloma, renal cell carcinoma, hepatocellular carcinoma, prostate carcinoma, pancreatic carcinoma, gliomas, nonsmall-cell lung cancer and mesotheliomas (10,39,40,41,42,43,44,45,46,47,48,49,50,51).…”

Updates on the Role of Molecular Alterations and NOTCH Signaling in the Development of Neuroendocrine Neoplasms

“…Despite the remarkable biological heterogeneity of NETs, the mammalian target of rapamycin (mTOR) molecular pathway has been found to be prominently altered in a vast majority of NETs [72]. The mTOR is a kinase-dependent signaling cascade, formed by the mTORC1 and mTORC2 multiprotein complexes, which main function is related with controlling cell growth.…”

“…The mTOR is a kinase-dependent signaling cascade, formed by the mTORC1 and mTORC2 multiprotein complexes, which main function is related with controlling cell growth. Mutations in NF1, TSC2 or PTEN-encoding for key suppressor's genes of this pathway and altered expression of mTOR pathway components are common hallmarks of a great proportion of NETs, wherein these alterations seem to be directly related with tumour development and progression [72].…”