Shukla Neerav, Somwar Romel, Smith Roger S, Ambati Sri, Munoz Stanley, Merchant Melinda, D'Arcy Padraig, Wang Xin, Kobos Rachel, Antczak Christophe, Bhinder Bhavneet, Shum David, Radu Constantin, Yang Guangbin, Taylor Barry S, Ng Charlotte K Y, Weigelt Britta, Khodos Inna, de Stanchina Elisa, Reis-Filho Jorge S, Ouerfelli Ouathek, Linder Stig, Djaballah Hakim, Ladanyi Marc
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Cancer Res. 2016 Aug 1;76(15):4525-34. doi: 10.1158/0008-5472.CAN-16-1040. Epub 2016 Jun 2.
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.
尤因肉瘤是一种原始圆形细胞肉瘤，在青少年中发病率最高，由EWSR1基因与ETS基因家族成员融合产生的嵌合致癌基因驱动。患有转移性和复发性疾病的患者预后不佳，需要更好的治疗选择。我们筛选了一个包含309,989种化合物的文库，以检测其对尤因肉瘤细胞生长的抑制作用，为开发新疗法提供依据，并发现可能拓宽我们对这种侵袭性肉瘤病理生物学理解的脆弱通路。此次筛选活动鉴定出一类苄基-4-哌啶酮化合物，它们通过诱导凋亡选择性抑制尤因肉瘤细胞系的生长。这些药物通过抑制去泛素化酶USP14和UCHL5来破坏19S蛋白酶体功能。尤因肉瘤细胞全基因组shRNA筛选的功能基因组数据也将蛋白酶体确定为尤因肉瘤细胞中的一个脆弱节点，为化学筛选结果提供了直系同源确认。此外，shRNA介导的尤因肉瘤细胞中USP14或UCHL5的沉默产生了显著的生长抑制。最后，用VLX1570（一种目前正在进行复发性多发性骨髓瘤临床试验的苄基-4-哌啶酮化合物衍生物）治疗尤因肉瘤异种移植小鼠模型，显著抑制了体内肿瘤生长。总体而言，我们的结果为使用19S蛋白酶体抑制剂作为尤因肉瘤的一种新治疗策略提供了临床前概念验证。《癌症研究》；76(15)；4525 - 34。©2016美国癌症研究协会。
