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

Abstract

Isabel Fernandes,1,2 Teresa R Pacheco,2 Adília Costa,3 Ana C Santos,2 Ana R Fernandes,3 Mara Santos,3 António G Oliveira,4 Sandra Casimiro,2 António Quintela,1 Afonso Fernandes,2 Madalena Ramos,3 Luís Costa1,21Department of Medical Oncology, Hospital Santa Maria, CHLN, Lisboa, Portugal; 2Clinical and Translational Oncology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; 3Department of Pathology, Hospital Santa Maria, CHLN, Lisboa, Portugal; 4Department of Biostatistics, Faculdade de Ciências Médicas, Universidade Nova, Lisboa, PortugalIntroduction: 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), phosphorylated (p)-AKT(Ser473), and p-S6(Ser240/244) was evaluated using immunohistochemistry in archival paraffin samples from 23 patients. Expression levels were correlated with clinicopathological 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.Keywords: mTOR pathway, neuroendocrine tumor, somatostatin analogs