Title |
Proteasome Addiction Defined in Ewing Sarcoma Is Effectively Targeted by a Novel Class of 19S Proteasome Inhibitors
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Published in |
Cancer Research, July 2016
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DOI | 10.1158/0008-5472.can-16-1040 |
Pubmed ID | |
Authors |
Neerav Shukla, Romel Somwar, Roger S. Smith, Sri Ambati, Stanley Munoz, Melinda Merchant, Padraig D'Arcy, Xin Wang, Rachel Kobos, Christophe Antczak, Bhavneet Bhinder, David Shum, Constantin Radu, Guangbin Yang, Barry S. Taylor, Charlotte K.Y. Ng, Britta Weigelt, Inna Khodos, Elisa de Stanchina, Jorge S. Reis-Filho, Ouathek Ouerfelli, Stig Linder, Hakim Djaballah, Marc Ladanyi |
Abstract |
Ewing's sarcoma (EWS) is a primitive round cell sarcoma with a peak incidence in adolescence that is driven by a chimeric oncogene created from the fusion of the EWSR1 gene with a member of the ETS family of genes. Patients with metastatic and recurrent disease have dismal outcomes and need better therapeutic options. We screened a library of 309,989 chemical compounds for growth inhibition of EWS cells to provide the basis for the development of novel therapies, and to discover vulnerable pathways that might broaden our understanding of the pathobiology of this aggressive sarcoma. This screening campaign identified a class of benzyl-4-piperidone compounds which selectively inhibit growth of EWS cell lines by inducing apoptosis. These agents disrupt 19S proteasome function through inhibition of the deubiquitinating enzymes USP14 and UCHL5. Functional genomic data from a genome-wide shRNA screen in EWS cells also identified the proteasome as a node of vulnerability in EWS cells, providing orthologous confirmation of the chemical screen findings. Furthermore, shRNA-mediated silencing of USP14 or UCHL5 in EWS cells produced significant growth inhibition. Finally, treatment of a xenograft mouse model of EMS with VLX1570, a benzyl-4-piperidone compound derivative currently in clinical trials for relapsed multiple myeloma, significantly inhibited in vivo tumor growth. Overall, our results offer a preclinical proof of concept for the use of 19S proteasome inhibitors as a novel therapeutic strategy for EWS. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 3 | 75% |
Unknown | 1 | 25% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 2 | 50% |
Scientists | 1 | 25% |
Science communicators (journalists, bloggers, editors) | 1 | 25% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 34 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Master | 5 | 15% |
Researcher | 4 | 12% |
Professor > Associate Professor | 4 | 12% |
Student > Bachelor | 3 | 9% |
Student > Ph. D. Student | 3 | 9% |
Other | 6 | 18% |
Unknown | 9 | 26% |
Readers by discipline | Count | As % |
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Agricultural and Biological Sciences | 7 | 21% |
Biochemistry, Genetics and Molecular Biology | 4 | 12% |
Medicine and Dentistry | 3 | 9% |
Computer Science | 2 | 6% |
Engineering | 2 | 6% |
Other | 4 | 12% |
Unknown | 12 | 35% |