Endocrine Abstracts

Mammalian target of rapamycin (mTOR), a main serine/threonine protein kinase in the phosphoinositide 3-kinase (PI3K)/Akt/p70S6K signalling pathway, is an important intracellular mediator involved in multiple cellular functions including proliferation, differentiation, apoptosis, tumorigenesis, angiogenesis, and also longevity.

Recent studies indicate that mTOR is central in the integration of a multitude of signalling pathways activated by growth factors and nutritional status, receiving stimulatory signals from Ras and PI3K. PI3K localizes Akt to the cell membrane where it can be phosphorylated and activated by PDK1. Activated Akt phosphorylates tuberin (TSC2), resulting in TSC1/2 complex instability and inhibition of the tumor suppressor function of the TSC2. Noteworthy, different components of the Ras/MAPK/ERK and PI3K signalling pathways are mutated in most human cancers, inducing abnormal regulation of mTOR signalling, and therefore possibly increasing its susceptibility to mTOR inhibitors. There is emerging data indicating that genetic and metabolic changes accompanying malignant transformation might cause hypersensitivity to mTOR inhibition. Rapamycin, a known immune suppressor and a macrocyclic lactone, and its derivatives temsirolimus (CCI-779), everolimus (RAD001) and deforolimus (AP23573), known as rapalogs, specifically inhibit the function of mTOR. Based on overexpression of the components of PI3K/Akt/mTOR signaling pathway in many different types of cancer, the use of mTOR inhibitors may result in effective anti-tumor activity in various endocrine tumor types. Combining an mTOR inhibitor with other anti-cancer drugs can sensitize endocrine tumor cells to these agents, producing additional activity and preventing drug resistance. The results of preclinical and phase I-II-III clinical studies show that mTOR inhibitors have promising anti-cancer activity, as single agents or in combination with other anti-tumor drugs, in neuroendocrine tumors.