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Supplementary Table 3 from Proteasome Addiction Defined in Ewing Sarcoma Is Effectively Targeted by a Novel Class of 19S Proteasome Inhibitors

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posted on 2023-03-31, 00:28 authored by 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

Results and analysis of a genome-wide functional genomic screen using the Sigma-Aldrich shRNA Human Genome Library consisting of 63,093 shRNAs targeting 11,748 human genes.

Funding

Ewing's Research Foundation, the Sarcoma Foundation of America, the Hyundai Hope on Wheels Program, the Ewing Sarcoma Research Fund

Commonwealth Foundation for Cancer Research

National Cancer Institute

History

ARTICLE ABSTRACT

Ewing sarcoma 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 Ewing sarcoma 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 that selectively inhibit the growth of Ewing sarcoma 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 Ewing sarcoma cells also identified the proteasome as a node of vulnerability in Ewing sarcoma cells, providing orthologous confirmation of the chemical screen findings. Furthermore, shRNA-mediated silencing of USP14 or UCHL5 in Ewing sarcoma cells produced significant growth inhibition. Finally, treatment of a xenograft mouse model of Ewing sarcoma 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 Ewing sarcoma. Cancer Res; 76(15); 4525–34. ©2016 AACR.

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