title: Targeting the mTOR Complex by Everolimus in NRAS Mutant Neuroblastoma.
abstract: High-risk neuroblastoma remains lethal in about 50% of patients despite multimodal treatment. Recent attempts to identify molecular targets for specific therapies have shown that Neuroblastoma RAS (NRAS) is significantly mutated in a small number of patients. However, few inhibitors for the potential treatment for NRAS mutant neuroblastoma have been investigated so far. In this in-vitro study, we show that MEK inhibitors AZD6244, MEK162 and PD0325901 block cell growth in NRAS mutant neuroblastoma cell lines but not in NRAS wild-type cell lines. Several studies show that mutant NRAS leads to PI3K pathway activation and combined inhibitors of PI3K/mTOR effectively block cell growth. However, we observed the combination of MEK inhibitors with PI3K or AKT inhibitors did not show synergestic effects on cell growth. Thus, we tested single mTOR inhibitors Everolimus and AZD8055. Interestingly, Everolimus and AZD8055 alone were sufficient to block cell growth in NRAS mutant cell lines but not in wild-type cell lines. We found that Everolimus alone induced apoptosis in NRAS mutant neuroblastoma. Furthermore, the combination of mTOR and MEK inhibitors resulted in synergistic growth inhibition. Taken together, our results show that NRAS mutant neuroblastoma can be targeted by clinically available Everolimus alone or in combination with MEK inhibitors which could impact future clinical studies.
authors.affiliation: Department of Gastroenterology and Hepatology, UniversityHospital Zurich, Zurich, Switzerland.|Department of Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Kiessling
authors.affiliation: Department of Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Curioni-Fontecedro
authors.affiliation: Department of Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Samaras
authors.affiliation: Department of Gastroenterology and Hepatology, UniversityHospital Zurich, Zurich, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lang
authors.affiliation: Department of Gastroenterology and Hepatology, UniversityHospital Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Scharl
authors.affiliation: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
authors.affiliation: Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Oldrige
authors.affiliation: Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America.
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.affiliation: Department of Gastroenterology and Hepatology, UniversityHospital Zurich, Zurich, Switzerland.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D000068338:Everolimus / Q000494:pharmacology*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C546842:MTOR protein, human; C579846:NRAS protein, human
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