PI(3)K–Akt–mTOR pathway as a potential therapeutic target in neuroendocrine tumors

Abstract

Constitutive activation of PI(3)K–Akt–mTOR signaling is a frequently occurring event in human cancer and has also been detected in the majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system. Molecular analysis of NETs suggests, that in addition to mutations in certain tumor-suppressor genes (e.g., PTEN), multiple autocrine growth factor loops contribute to hyperactive PI(3)K–Akt–mTOR signaling, thus promoting unrestricted proliferation and resistance to apoptosis. These insights opened new perspectives for targeted therapy in NETs. In particular, several novel small-molecule inhibitors of tyrosine and serine/threonine kinases have demonstrated potent anti-tumor activity. This review will summarize current knowledge on PI(3)K–Akt–mTOR signaling, its role in proliferation and apoptosis, as well as novel therapeutic approaches targeting PI(3)K–Akt–mTOR pathway components in NET disease.

Keywords::

• apoptosis resistance
• growth factors
• kinase inhibitors
• neuroendocrine tumor
• PI(3)K–Akt–mTOR signaling
• proliferation
• receptor tyrosine kinase
• targeted therapy

Financial & competing interests disclosure

CJ Auernhammer receives grant support and consulting fees from Novartis and Ipsen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.