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. Cancer Res; 76(15); 4525-34. ©2016 AACR.
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York. shuklan@mskcc.org.
authors.forename: Neerav
authors.initials: N
authors.lastname: Shukla
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Romel
authors.initials: R
authors.lastname: Somwar
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Smith
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sri
authors.initials: S
authors.lastname: Ambati
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Stanley
authors.initials: S
authors.lastname: Munoz
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Melinda
authors.initials: M
authors.lastname: Merchant
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Padraig
authors.initials: P
authors.lastname: D'Arcy
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Rachel
authors.initials: R
authors.lastname: Kobos
authors.affiliation: High-Throughput Drug Screening Facility, Memorial Sloan Kettering Cancer Center, New YorkNew York.
authors.forename: Christophe
authors.initials: C
authors.lastname: Antczak
authors.affiliation: High-Throughput Drug Screening Facility, Memorial Sloan Kettering Cancer Center, New YorkNew York.
authors.forename: Bhavneet
authors.initials: B
authors.lastname: Bhinder
authors.affiliation: High-Throughput Drug Screening Facility, Memorial Sloan Kettering Cancer Center, New YorkNew York.
authors.forename: David
authors.initials: D
authors.lastname: Shum
authors.affiliation: High-Throughput Drug Screening Facility, Memorial Sloan Kettering Cancer Center, New YorkNew York.
authors.forename: Constantin
authors.initials: C
authors.lastname: Radu
authors.affiliation: Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Guangbin
authors.initials: G
authors.lastname: Yang
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.affiliation: Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Inna
authors.initials: I
authors.lastname: Khodos
authors.affiliation: Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.affiliation: Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ouathek
authors.initials: O
authors.lastname: Ouerfelli
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, Sweden. Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
authors.affiliation: High-Throughput Drug Screening Facility, Memorial Sloan Kettering Cancer Center, New YorkNew York.
authors.forename: Hakim
authors.initials: H
authors.lastname: Djaballah
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex