Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) originate from neuroendocrine cells in the gastrointestinal tract. They are heterogeneous, and though initially considered rare tumors, the incidence of GEP-NENs has increased in the last few decades. Therapeutic approaches for the metastatic disease include surgery, radiological intervention by chemoembolisation, radiofrequency ablation, biological therapy in addition to somatostatin analogs, and PRRT therapy (177Lu-DOTATATE). The PI3K-AKT-mTOR pathway is essential in the regulation of protein translation, cell growth, and metabolism. Evidence suggests that the mTOR pathway is involved in malignant progression and resistance to treatment through over-activation of several mechanisms. PI3K, one of the main downstream of the Akt-mTOR axis, is mainly involved in the neoplastic process. This pathway is frequently deregulated in human tumors, making it a central target in the development of new anti-cancer treatments. Recent molecular studies identify potential targets within the PI3K/Akt/mTOR pathway in GEP-NENs. However, the use of target therapy has been known to lead to resistance due to several mechanisms such as feedback activation of alternative pathways, inactivation of protein kinases, and deregulation of the downstream mTOR components. Therefore, the specific role of targeted drugs for the management of GEP-NENs is yet to be well-defined. The variable clinical presentation of advanced neuroendocrine tumors is a significant challenge for designing studies. This review aims to highlight the role of the PI3K/Akt/mTOR pathway in the development of neuroendocrine tumors and further specify its potential as a therapeutic target in advanced stages.
Highlights
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are defined as a heterogeneous group of neoplasia that originates from neuroendocrine cells widely dispersed throughout the gastrointestinal tract forming the largest group of hormone-producing cells in the body [1, 2]
The results showed good tolerability with no differences in median progression-free survival (PFS) between the two groups (Everolimus followed by sunitinib, 36.5 months vs. Sunitinib followed by Everolimus, 31.6 months) [62]
The use of Everolimus has been known to lead to resistance due to several mechanisms such as feedback activation of alternative pathways, inactivation of protein kinases, and deregulation of the downstream mTOR components [108, 109] Next-generation mTOR inhibitors have been studied to avoid the mechanisms of resistance and reduce the drug toxicity [85]
Summary
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are defined as a heterogeneous group of neoplasia that originates from neuroendocrine cells widely dispersed throughout the gastrointestinal tract forming the largest group of hormone-producing cells in the body [1, 2]. On the contrary, during the same period, progress in diagnosis has only been matched by a modest improvement in outcomes due to [5] GEP-NENs often being unpredictable and unusual in terms of symptoms, disease progression, and overall survival [6]. The consequence of late diagnosis (5–7 years on average) is that 75% of tumors exhibit synchronous liver metastases at the time of diagnosis [7, 8]. 50% of the tumors are asymptomatic until late presentation with symptoms of mass effects or distant metastases, frequently hepatic, or both or tumor-induced fibrosis [9]
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