Expression of mTOR signaling pathway and effects of mTOR inhibitors on its pathway in human neuroendocrine tumors

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Introduction: Neuroendocrine tumors (NET), especially well-differentiated endocrine tumors, are often slow-growing, indolent, and may not become clinically apparent until the manifestations of metastatic spread or carcinoid syndrome. Results of previous studies demonstrated that phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway may be activated in the great majority of NET cells. mTOR inhibitors are therefore considered effective anti-tumor reagents but they may also induce an activation of PI3K/Akt and MAPK pathways as a compensatory action and reduce their own anti-tumor activities.

Aim(s): To evaluate and analyze the expression of mTOR signaling pathways in NET specimens. We also characterized the effects of mTOR inhibitors (mTORi) with or without MAPK/ERK kinase (MEK) inhibitors (MEKi) in human NET cell lines, in order to pursue the significance of mTOR inhibition in NET.

Materials and methods: We first evaluated the expression of activated (phosphorylated =p)-ERK, mTOR and its downstream factors (4EBP1 and S6) in 72 NET cases using immunohistochemistry (IHC) and hierarchical clustering analysis was subsequently applied to the analysis. We then evaluated the anti-tumor activities and its mechanism of mTORi (RAD001; Novartis) with/without MEKi (U0126; SIGMA) in bronchial and colon human NET cell lines (NCI-H727 and COLO320, respectively) using MTT assay and immunoblotting. We further examined the effects of invasion/migration activities of NET using wound-healing assay.

Conference: 7th Annual ENETSConcerence (2010)

Presenting Author: Sasano H

Authors: Iida S, Miki Y, Ono K, Sasano H,

Keywords: neuroendocrine tumors, mTOR inhibitors, MEK inhibitors, combination therapy,