Iyer Rema, Deshpande Anagha, Pedgaonkar Aditi, Bala Pramod Akula, Kim Taehee, Brien Gerard L, Finlay Darren, Vuori Kristiina, Soragni Alice, Wetterstein Hiromi I, Murad Rabi, Deshpande Aniruddha J
Cancer Genome and Epigenetics Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
Computational Biology Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
EMBO J. 2025 Aug 13. doi: 10.1038/s44318-025-00526-w.
Synovial sarcoma (SySa) is an aggressive soft tissue sarcoma with an urgent need to develop targeted therapies. Here, we exploited specific vulnerabilities created by transcriptional rewiring by the fusion protein SS18::SSX, the sole oncogenic driver in SySa. To uncover genes that are selectively essential for the fitness of SySa cells compared to other tumor cell lines, we mined the Cancer-Dependency-Map data. Targeted CRISPR library screening of SySa-selective candidates revealed that the small ubiquitin-like modifier 2 (SUMO2) constituted one of the strongest dependencies both in vitro and in vivo. TAK-981, a clinical-stage small-molecule SUMO2 inhibitor potently suppressed growth and colony-forming ability. Transcriptomic profiling showed that SUMO2 inhibition elicited a profound reversal of the gene expression program orchestrated by SS18::SSX fusion. Further, genetic depletion or SUMO2 inhibition reduced global expression levels and chromatin occupancy of the SS18::SSX fusion protein with a concomitant reduction in histone 2A lysine 119 ubiquitination (H2AK119ub), an epigenetic mark facilitating SySa pathogenesis. Taken together, our study identifies SUMO2 as a novel, selective vulnerability in synovial sarcoma, suggesting new avenues for targeted treatment of soft tissue tumors.
滑膜肉瘤（SySa）是一种侵袭性软组织肉瘤，迫切需要开发靶向治疗方法。在此，我们利用了由融合蛋白SS18::SSX转录重排产生的特定脆弱性，SS18::SSX是滑膜肉瘤中唯一的致癌驱动因子。为了找出与其他肿瘤细胞系相比，对滑膜肉瘤细胞适应性具有选择性重要作用的基因，我们挖掘了癌症依赖性图谱数据。对滑膜肉瘤选择性候选基因进行靶向CRISPR文库筛选发现，小泛素样修饰物2（SUMO2）在体外和体内都是最强的依赖性因素之一。TAK-981是一种临床阶段的小分子SUMO2抑制剂，能有效抑制生长和集落形成能力。转录组分析表明，SUMO2抑制引发了由SS18::SSX融合蛋白精心编排的基因表达程序的深刻逆转。此外，基因敲除或SUMO2抑制降低了SS18::SSX融合蛋白的整体表达水平和染色质占有率，同时组蛋白2A赖氨酸119泛素化（H2AK119ub）减少，H2AK119ub是一种促进滑膜肉瘤发病机制的表观遗传标记。综上所述，我们的研究确定SUMO2是滑膜肉瘤中一种新的选择性脆弱因素，为软组织肿瘤的靶向治疗提供了新途径。
