Abstract
Approximately 30-50% of individuals with Neurofibromatosis type 1 develop benign peripheral nerve sheath tumors, called plexiform neurofibromas (PNFs). PNFs can undergo malignant transformation to highly metastatic malignant peripheral nerve sheath tumors (MPNSTs) in 5-10% of NF1 patients, with poor prognosis. No effective systemic therapy is currently available for unresectable tumors. In tumors, the NF1 gene deficiency leads to Ras hyperactivation causing the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and inducing multiple cellular responses including cell proliferation. In this study, three NF1-null MPNST-derived cell lines (90-8, 88-14 and 96-2), STS26T sporadic MPNST cell line and PNF-derived primary Schwann cells were used to test responses to AZD8055, an ATP-competitive "active-site" mTOR inhibitor. In contrast to rapamycin treatment which only partially affected mTORC1 signaling, AZD8055 induced a strong inhibition of mTORC1 and mTORC2 signaling in MPNST-derived cell lines and PNF-derived Schwann cells. AZD8055 induced full blockade of mTORC1 leading to an efficient decrease of global protein synthesis. A higher cytotoxic effect was observed with AZD8055 compared to rapamycin in the NF1-null MPNST-derived cell lines with IC50 ranging from 70 to 140 nM and antiproliferative effect was confirmed in PNF-derived Schwann cells. Cell migration was impaired by AZD8055 treatment and cell cycle analysis showed a G0/G1 arrest. Combined effects of AZD8055 and PD0325901 MEK inhibitor as well as BRD4 (BromoDomain-containing protein 4) inhibitors showed a synergistic antiproliferative effect. These data suggest that NF1-associated peripheral nerve sheath tumors are an ideal target for AZD8055 as a single molecule or in combined therapies.
Keywords:
MPNST; NF1; dual mTORC1/2 inhibitor; plexiform neurofibromas.
MeSH terms
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Benzamides / pharmacology
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects*
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Diphenylamine / analogs & derivatives
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Diphenylamine / pharmacology
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Drug Synergism
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G1 Phase Cell Cycle Checkpoints / drug effects
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Humans
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Inhibitory Concentration 50
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MAP Kinase Kinase 1 / antagonists & inhibitors
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MAP Kinase Kinase 1 / metabolism
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MAP Kinase Kinase 2 / antagonists & inhibitors
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MAP Kinase Kinase 2 / metabolism
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Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors*
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Mechanistic Target of Rapamycin Complex 2 / antagonists & inhibitors*
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Morpholines / pharmacology*
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Morpholines / therapeutic use
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Nerve Sheath Neoplasms / drug therapy*
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Nerve Sheath Neoplasms / etiology
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Nerve Sheath Neoplasms / genetics
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Neurofibroma, Plexiform / drug therapy*
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Neurofibroma, Plexiform / etiology
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Neurofibroma, Plexiform / genetics
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Neurofibromatosis 1 / complications
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Neurofibromatosis 1 / genetics
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Neurofibromin 1 / genetics
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Nuclear Proteins / metabolism
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Primary Cell Culture
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins c-akt / metabolism
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Schwann Cells
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Signal Transduction / drug effects
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Sirolimus / pharmacology
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Sirolimus / therapeutic use
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / metabolism
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Transcription Factors / metabolism
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ras Proteins / metabolism
Substances
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Antineoplastic Agents
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BRD4 protein, human
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Benzamides
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Cell Cycle Proteins
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Morpholines
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Neurofibromin 1
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Nuclear Proteins
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Protein Kinase Inhibitors
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Transcription Factors
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mirdametinib
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(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
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Diphenylamine
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MAP2K2 protein, human
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MTOR protein, human
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP2K1 protein, human
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ras Proteins
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Sirolimus