title: Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells.
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.
authors: EA7331, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Jennifer
authors: J
authors: Varin
authors: Institut Cochin, Département d'Immuno-Hématologie, CNRS UMR8104, INSERM U1016, Paris, France.
authors: Laury
authors: L
authors: Poulain
authors: Service de Chirurgie Plastique et Reconstructrice, Hôpital Européen Georges Pompidou- AP-HP, Université Paris Descartes, Paris, France.
authors: Mikael
authors: M
authors: Hivelin
authors: Service de Biochimie et de Génétique Moléculaire, Hôpital Cochin, AP-HP, Paris, France.
authors: Patrick
authors: P
authors: Nusbaum
authors: Service de Biochimie et de Génétique Moléculaire, Hôpital Cochin, AP-HP, Paris, France.
authors: Arnaud
authors: A
authors: Hubas
authors: EA7331, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Ingrid
authors: I
authors: Laurendeau
authors: Service de Chirurgie Plastique et Reconstructrice, Hôpital Européen Georges Pompidou- AP-HP, Université Paris Descartes, Paris, France.
authors: Laurent
authors: L
authors: Lantieri
authors: Département de Dermatologie, Centre de Référence des Neurofibromatoses, Hôpital Henri-Mondor, AP-HP , Créteil, France.|EA 4393 LIC, Université Paris Est Créteil (UPEC), Créteil, France.
authors: Pierre
authors: P
authors: Wolkenstein
authors: EA7331, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Service de Biochimie et de Génétique Moléculaire, Hôpital Cochin, AP-HP, Paris, France.
authors: Michel
authors: M
authors: Vidaud
authors: EA7331, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Service de Biochimie et de Génétique Moléculaire, Hôpital Cochin, AP-HP, Paris, France.
authors: Eric
authors: E
authors: Pasmant
authors: Institut Cochin, Département d'Immuno-Hématologie, CNRS UMR8104, INSERM U1016, Paris, France.|Service d'Hématologie Biologique, Hôpital Cochin, AP-HP, Paris, France.
authors: Nicolas
authors: N
authors: Chapuis
authors: EA7331, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Service de Biochimie et de Génétique Moléculaire, Hôpital Cochin, AP-HP, Paris, France.
authors: Béatrice
authors: B
authors: Parfait
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000037:antagonists & inhibitors*; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D018318:Neurofibroma, Plexiform / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000150:complications / Q000235:genetics; D025542:Neurofibromin 1 / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012583:Schwann Cells; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018797:Cell Cycle Proteins; D004159:Diphenylamine; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D009025:Morpholines; D025542:Neurofibromin 1; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D018631:ras Proteins; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C506614:mirdametinib; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C482128:MAP2K2 protein, human; C546842:MTOR protein, human; C482125:MAP2K1 protein, human
keywords: MPNST; NF1; dual mTORC1/2 inhibitor; plexiform neurofibromas