The
mammalian target of rapamycin (mTOR) pathway may constitute a potential target for the treatment of
malignant peripheral nerve sheath tumors (
MPNST). However, investigations of other
cancers suggest that mTOR blockade can paradoxically induce activation of prosurvival, protumorigenic signaling molecules, especially upstream AKT. Consequently, we hypothesized that dual
phosphatidylinositol 3-kinase (PI3K)/AKT-mTOR blockade might be applicable for
MPNST treatment. Expression of activated mTOR downstream targets (p4EBP1 and pS6RP) and pAKT was evaluated immunohistochemically in a tissue microarray of human MPNSTs (n = 96) and benign
neurofibromas (n = 31). Results were analyzed by Wilcoxon rank-sum tests. mTOR and AKT pathways in human
MPNST cell lines, and the effects of
rapamycin (mTOR inhibitor),
LY294002 (dual PI3K/mTOR inhibitor), and
PI-103 (potent dual PI3K/AKT-mTOR inhibitor) on pathway activation were evaluated by Western blot. Effects on cell growth were evaluated via MTS and colony formation assays. Cell cycle progression and apoptosis were assessed by
propidium iodide/fluorescence-activated cell sorting staining and
Annexin V assays.
Acridine orange staining/fluorescence-activated cell sorting analysis, electron microscopy, and Western blot evaluated autophagy induction. p4EBP1, pS6Rp, and pAKT levels were found to be significantly higher in
MPNST versus
neurofibroma (P < 0.05 for all markers). mTOR and AKT pathways were found to be highly activated in
MPNST cell lines.
MPNST cells were sensitive to
rapamycin; however,
rapamycin enhanced pAKT and peIF4E expression.
PI-103 abrogated
MPNST cell growth and induced G(1) cell cycle arrest potentially through repression of
cyclin D1.
PI-103 did not elicit apoptosis but significantly induced autophagy in
MPNST cells. These results suggest further study of combined PI3K/AKT and mTOR inhibition as a novel
therapy for patients harboring
MPNST.