Dual targeting of AKT and mammalian target of rapamycin: a potential therapeutic approach for malignant peripheral nerve sheath tumor.
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.
Zou
Changye Y
CY
Department of Surgical Oncology, The University of Texas M. D. AndersonCancer Center, Houston, Texas 77030, USA.
Smith
Kerrington D
KD
Zhu
Quan-Sheng
QS
Liu
Jun
J
McCutcheon
Ian E
IE
Slopis
John M
JM
Meric-Bernstam
Funda
F
Peng
Zhenghong
Z
Bornmann
William G
WG
Mills
Gordon B
GB
Lazar
Alexander J
AJ
Pollock
Raphael E
RE
Lev
Dina
D
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D005663:Furans / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D018317:Nerve Sheath Neoplasms / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005663:Furans; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011743:Pyrimidines; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C111931:ELF4 protein, human; C522973:PI103