Proteasome addiction defined in Ewing sarcoma is effectively targeted by a novel class of 19S proteasome inhibitors Journal Article
| Authors: | Shukla, N.; Somwar, R.; Smith, R. S.; Ambati, S.; Munoz, S.; Merchant, M.; D'Arcy, P.; Wang, X.; Kobos, R.; Antczak, C.; Bhinder, B.; Shum, D.; Radu, C.; Yang, G.; Taylor, B. S.; Ng, C. K. Y.; Weigelt, B.; Khodos, I.; De Stanchina, E.; Reis-Filho, J. S.; Ouerfelli, O.; Linder, S.; Djaballah, H.; Ladanyi, M. |
| Article Title: | Proteasome addiction defined in Ewing sarcoma is effectively targeted by a novel class of 19S proteasome inhibitors |
| 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. ©2016 AACR. |
| Keywords: | controlled study; unclassified drug; nonhuman; antineoplastic agent; mouse; animal tissue; apoptosis; proteasome; proteasome inhibitor; enzyme inhibition; animal experiment; animal model; in vivo study; in vitro study; tumor xenograft; ewing sarcoma; cancer inhibition; drug mechanism; mitosis inhibition; female; priority journal; article; deubiquitinase; 19s proteasome; b ap 15; protein uchl5; protein usp14; vlx 1570 |
| Journal Title: | Cancer Research |
| Volume: | 76 |
| Issue: | 15 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2016-08-01 |
| Start Page: | 4525 |
| End Page: | 4534 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-16-1040 |
| PROVIDER: | scopus |
| PUBMED: | 27256563 |
| PMCID: | PMC5484002 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2016 -- Source: Scopus |
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