title: Combinatorial Drug Screening Identifies Ewing Sarcoma-specific Sensitivities.
abstract: Improvements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any associated adverse side effects through reduced dosing, which is particularly important in childhood tumors. Using a parallel phenotypic combinatorial screening approach of cells derived from three pediatric tumor types, we identified Ewing sarcoma-specific interactions of a diverse set of targeted agents including approved drugs. We were able to retrieve highly synergistic drug combinations specific for Ewing sarcoma and identified signaling processes important for Ewing sarcoma cell proliferation determined by EWS-FLI1 We generated a molecular target profile of PKC412, a multikinase inhibitor with strong synergistic propensity in Ewing sarcoma, revealing its targets in critical Ewing sarcoma signaling routes. Using a multilevel experimental approach including quantitative phosphoproteomics, we analyzed the molecular rationale behind the disease-specific synergistic effect of simultaneous application of PKC412 and IGF1R inhibitors. The mechanism of the drug synergy between these inhibitors is different from the sum of the mechanisms of the single agents. The combination effectively inhibited pathway crosstalk and averted feedback loop repression, in EWS-FLI1-dependent manner. Mol Cancer Ther; 16(1); 88-101. ©2016 AACR.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Branka
authors.initials: B
authors.lastname: Radic-Sarikas
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Department of Oncology, Georgetown University Medical Center, Washington, DC.
authors.forename: Kalliopi P
authors.initials: KP
authors.lastname: Tsafou
authors.affiliation: Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kristina B
authors.initials: KB
authors.lastname: Emdal
authors.affiliation: School of Mathematics and Statistics, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Theodore
authors.initials: T
authors.lastname: Papamarkou
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Kilian V M
authors.initials: KV
authors.lastname: Huber
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Mutz
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Toretsky
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.affiliation: Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jesper V
authors.initials: JV
authors.lastname: Olsen
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.|Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Kovar
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. gsuperti@cemm.oeaw.ac.at.|Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D004195:Disease Models, Animal; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D058990:Molecular Targeted Therapy; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D040901:Proteomics / Q000379:methods; D051789:Proto-Oncogene Protein c-fli-1 / Q000037:antagonists & inhibitors; D034802:RNA-Binding Protein EWS / Q000037:antagonists & inhibitors; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C106031:EWS-FLI fusion protein; C000597236:IGF1R protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D017451:Receptors, Somatomedin; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D019311:Staurosporine; C059539:midostaurin