Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells
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Jennifer Varin1,*, Laury Poulain2,*, Mikael Hivelin3, Patrick Nusbaum4, Arnaud Hubas4, Ingrid Laurendeau1, Laurent Lantieri3, Pierre Wolkenstein5,6, Michel Vidaud1,4, Eric Pasmant1,4, Nicolas Chapuis2,7 and Béatrice Parfait1,4
1 EA7331, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
2 Institut Cochin, Département d’Immuno-Hématologie, CNRS UMR8104, INSERM U1016, Paris, France
3 Service de Chirurgie Plastique et Reconstructrice, Hôpital Européen Georges Pompidou- AP-HP, Université Paris Descartes, Paris, France
4 Service de Biochimie et de Génétique Moléculaire, Hôpital Cochin, AP-HP, Paris, France
5 Département de Dermatologie, Centre de Référence des Neurofibromatoses, Hôpital Henri-Mondor, AP-HP, Créteil, France
6 EA 4393 LIC, Université Paris Est Créteil (UPEC), Créteil, France
7 Service d’Hématologie Biologique, Hôpital Cochin, AP-HP, Paris, France
* These authors have contributed equally to this work
Béatrice Parfait, email:
Keywords: dual mTORC1/2 inhibitor, NF1, MPNST, plexiform neurofibromas
Received: August 17, 2015 Accepted: January 19, 2016 Published: January 31, 2016
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.
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