Combinatorial drug screening identifies Ewing sarcoma-specific sensitivities

Radic-Sarikas, B. et al. (2017) Combinatorial drug screening identifies Ewing sarcoma-specific sensitivities. Molecular Cancer Therapeutics, 16(1), pp. 88-101. (doi: 10.1158/1535-7163.MCT-16-0235) (PMID:28062706)

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.

• Item Type: Articles
• Additional Information: B. Radic-Sarikas, K.P. Tsafou, K.B. Emdal, T. Papamarkou, K.V.M. Huber, J.V. Olsen, S. Brunak, H. Kovar and G. Superti-Furga were funded by the European Union Seventh Framework Programme (FP7/2007- 2013) ASSET project under grant agreement number FP7- HEALTH-2010-259348-2. C. Mutz was funded by FWF ERA-Net grant I1225-B19. K.L. Bennett was supported by the Austrian Academy of Sciences.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Papamarkou, Dr Theodore
• Authors: Radic-Sarikas, B., Tsafou, K. P., Emdal, K. B., Papamarkou, T., Huber, K. V.M., Mutz, C., Toretsky, J. A., Bennett, K. L., Olsen, J. V., Brunak, S., Kovar, H., and Superti-Furga, G.
• College/School: College of Science and Engineering > School of Mathematics and Statistics > Statistics
• Journal Name: Molecular Cancer Therapeutics
• Publisher: American Association for Cancer Research
• ISSN: 1535-7163
• ISSN (Online): 1538-8514
• Published Online: 15 November 2016
• Copyright Holders: Copyright © 2016 American Association for Cancer Research
• First Published: First published in Molecular Cancer Therapeutics 16(1): 88-101
• Publisher Policy: Reproduced in accordance with the publisher copyright policy