Prognostic significance of AKT/mTOR signaling in advanced neuroendocrine tumors treated with somatostatin analogs

Introduction: Somatostatin analogs (SSAs) are used as part of standard treatment for advanced neuroendocrine tumors (NETs). The mechanisms behind the antiproliferative action of SSAs remain largely unknown, but a connection with the mammalian target of rapamycin (mTOR) signaling pathway has been sug...

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Bibliographic Details
Main Author: Fernandes, Isabel (author)
Other Authors: Pacheco, Teresa R. (author), Costa, Adília (author), Santos, Ana C. (author), Fernandes, Ana R. (author), Santos, Mara (author), Oliveira, António G. (author), Casimiro, Sandra (author), Quintela, António (author), Fernandes, Afonso (author), Ramos, Madalena (author), Costa, Luís (author)
Format: article
Language:eng
Published: 2017
Subjects:
MTOR pathway
Neuroendocrine tumor
Somatostatin analogs
Oncology
Pharmacology (medical)
Online Access:https://doi.org/10.2147/OTT.S36330
Country:Portugal
Oai:oai:run.unl.pt:10362/24690
Description
Summary:Introduction: Somatostatin analogs (SSAs) are used as part of standard treatment for advanced neuroendocrine tumors (NETs). The mechanisms behind the antiproliferative action of SSAs remain largely unknown, but a connection with the mammalian target of rapamycin (mTOR) signaling pathway has been suggested. Our purpose was to evaluate the activation status of the AKT/mTOR pathway in advanced metastatic NETs and identify biomarkers of response to SSA therapy. Patients and methods: Expression of phosphatase and tensin homolog (PTEN), phospho-rylated (p)-AKT(Ser473), and p-S6(Ser240/244) was evaluated using immunohistochemistry in archival paraffin samples from 23 patients. Expression levels were correlated with clinico-pathological parameters and progression-free survival under treatment with SSAs. Results: A positive association between p-AKT and p-S6 expression was identified (P = 0.01) and higher expression of both markers was observed in pancreatic NETs. AKT/mTOR activation was observed without the loss of PTEN expression. Tumors showing AKT/mTOR signaling activation progressed faster when treated with SSAs: higher expression of p-AKT or p-S6 predicted a median progression-free survival of 1 month vs 26.5 months for lower expression (P = 0.02). Conclusion: Constitutive activation of the AKT/mTOR pathway was associated with shorter time-to-progression in patients undergoing treatment with SSAs. Larger case series are needed to validate whether p-AKT(Ser473) and p-S6(Ser240/244) can be used as prognostic markers of response to therapy with SSAs.

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