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Mol Cancer Ther. 2017 Jan;16(1):88-101. doi: 10.1158/1535-7163.MCT-16-0235. Epub 2016 Nov 15.

Combinatorial Drug Screening Identifies Ewing Sarcoma-specific Sensitivities.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
2
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
3
Department of Oncology, Georgetown University Medical Center, Washington, DC.
4
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
5
School of Mathematics and Statistics, University of Glasgow, Glasgow, United Kingdom.
6
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
7
Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
8
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. gsuperti@cemm.oeaw.ac.at.
9
Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.

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.

PMID:
28062706
DOI:
10.1158/1535-7163.MCT-16-0235
[Indexed for MEDLINE]
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