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

Abstract

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), 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.

RABL6A inhibits tumor-suppressive PP2A/AKT signaling to drive pancreatic neuroendocrine tumor growth

“…Prominent cancer pathways affected in patient tumors and similarly regulated by RABL6A included p53, RB1, and AKT (Table 1). Having previously examined the importance of p53 and RB1 in RABL6A function in PNETs (23), we focused on the AKT pathway, a major driver of PNET pathogenesis (14)(15)(16)(17)(18). Ingenuity Pathway Analysis (IPA) of the gene expression profiles from RABL6A knockdown (KD) versus control BON-1 cells suggested that loss of RABL6A expression impaired AKT pathway activation ( Figure 1B).…”

“…The clinical use of everolimus in patients with advanced PNETs (10)(11)(12)(13) was based on evidence that hyperactivation of PI3-kinase (PI3K)/AKT/mTOR signaling is central to PNET progression and associated with worse patient outcomes (14)(15)(16)(17)(18). Tumors harbor mutations in pathway genes (e.g., PIK3CA, TSC2, and PTEN) (14,18) and dysregulation of the proteins is common, including downregulation of the PTEN and TSC2 tumor suppressors and increased phosphorylation of AKT and mTORC1 kinase targets/effectors (S6K, S6, and EIF4EBP1) (15)(16)(17). Everolimus therapy significantly increases median progression-free survival and, although not statistically significant, is associated with a 6-month improvement in median overall survival (to 44 months) compared with placebo (11,12).…”

Somatostatin Analogue Treatment Primarily Induce miRNA Expression Changes and Up-Regulates Growth Inhibitory miR-7 and miR-148a in Neuroendocrine Cells

“…However, the molecular mechanisms linking neuroendocrine proliferation and tumor progression are not yet fully understood. The PI3K/MAPK/mTOR pathway is known to play an important role in NETs [ 43 , 44 ]. Already existing therapies used to treat patients with NETs consist of agents targeting this specific signaling pathway [ 45 , 46 , 47 , 48 , 49 ].…”

Critical focus on mechanisms of resistance and toxicity of m-TOR inhibitors in pancreatic neuroendocrine tumors

“…Over the last years, several studies, both in preclinical models and in tumoral tissue, reported a role for mTOR as a prognostic and potentially predictive biomarker [2,[8][9][10][11][12]: Fernandes and colleagues evaluated the prognostic significance of AKT/mTOR signaling using immunohistochemistry in archival paraffin samples of advanced NETs treated with somatostatin analogs (SSAs). They found that tumors with high mTOR activation progressed faster when treated with SSAs, in particular, the higher expression of p-AKT or p-S6 predicted a median PFS of 1 month vs 26.5 months compared with patients with a lower expression [8]. Data obtained from similar studies conducted on archivial tissue suggested that mTOR is not only a "druggable" biomarker but also a possible site of resistance to SSA.…”