mTOR Pathway in Gastroenteropancreatic Neuroendocrine Tumor (GEP-NETs)

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.

Keywords: GEP-NENs; GEP-NETs; cancer treatment; mTOR; neuroendocrine tumor; target therapy.

Figure 1

The PI3K/Akt/mTOR pathway. Following growth factors stimulation and subsequent activation of RTKs and GPCRs, PI3K is recruited to the plasma membrane directly or through adaptor protein and phosphorylated PIP2 producing PIP3, which recruits and activates PDK1. Akt activation is mediated by PDK1 on T308 and by mTORC2 complex on S473. Akt controls the activity of mTORC1 inactivating the GTPase activity of the TSC1/TSC2 complex toward the mTORC1 activator Rheb. mTORC1 activation induces protein synthesis via p70S6K and 4EBP1. The tumor suppressor gene PTEN acts on this pathway antagonizing the PI3K action on PIP3.

Figure 2

mTORC 1 and 2 are inhibited by different classes of mTOR inhibitors: Rapalogs are the first generation mTORC inhibitors able to induce a partial inhibition of mTORC1. The second and third generation act on both mTORC1 and 2. TORki blocks the ATP binding sites of the complexes, while Rapalinks act through blocking the ATP binding site and by the inhibition of the mTORC1.

Figure 3

Agents used in combination with mTORC1 inhibitors: Protein kinase inhibitors, Sorafenib and Sunitinib are active against several tyrosine kinases receptors (RTKs) including VEGFR and PDGFR. Sorafenib can also inhibit RAF kinases. The monoclonal antibody Bevacizumab inhibits angiogenic pathway binding VEGFA and avoiding VEGFRs activation. Somatostatin analogs bind somatostatin receptors impairing cell growth while Rapalogues can inhibit mTORC1.

Figure 4

Proposed mechanisms for resistance to Rapalogues in NET. 1- Inhibition of mTOR results in PI3k-Akt-mTOR pathway reactivation and MAPK pathway activation. 2- Inactivating mutations in TSC1/2 cause the inactivation of the TSC1/TSC2 protein complex leading to mTOR hyperactivation. 3- mTOR inhibitor treatment cause an increase in tyrosine kinase receptors and growth factor secretion. 4- GSK3 over-expression accompanied by the decrease of IRS-1 protein leads to decreased autophagy and cell resistance to Everolimus. 5- The up-regulation of angiogenic factors mTOR-independent or the re-expression of HIFα.