Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in synovial sarcoma [SY18_ChIP-seq]

Synovial Sarcoma (SS) is driven by the SS18::SSX translocation event and is often diagnosed in patients under 30. In general, SS is refractory to chemotherapy and other therapeutic approaches. SS18::SSX does not directly bind to DNA. Instead, SS18::SSX alters ATP-dependent chromatin remodeling complex BAF (mammalian SWI/SNF complex) complexes away from a wild-type SS18-containing canonical (cBAF) complex towards a SS18::SSX-containing non-canonical (nc)BAF complex to drive a SS-specific transcription program with subsequent tumor formation. Small molecule targeted therapies are expanding beyond the kinome, providing additional tools to treat cancers that are not yet amenable to targeted therapies. Here, we demonstrate that SS18::SSX activates the SUMOylation program and SS are sensitive to the small molecule SAE1/2 inhibitor, TAK-981 (subasumstat). Mechanistically, we demonstrate TAK-981 de-SUMOylates the cBAF and Polybromo-associated BAF complex (PBAF) complex member, SMARCE1. The result of which is stabilization and restoration of cBAF complexes on chromatin, shifting away from the dominant SS18::SSX-ncBAF-complex driven transcriptome. This phenotypic shift is associated with DNA damage and cell death, resulting in tumor inhibition across both human and mouse SS tumor models. As such, TAK-981 combined with standard-of-care chemotherapy enhances induced synergistic activity through increased DNA damage, leading to tumor regressions. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, and positioning the in-clinic TAK-981 as a novel candidate to treat this refractory cancer. Chromatin Immunoprecipitation DNA sequencing (ChIP seq) for SS18::SSX, SMARCA4, KDM2B and H3K27ac in SYO.1 and SYO.1 synovial sarcoma cell lines

滑膜肉瘤（Synovial Sarcoma, SS）由SS18::SSX易位事件驱动，多发于30岁以下患者。通常情况下，SS对化疗及其他治疗手段均表现为难治性。SS18::SSX无法直接结合DNA，而是通过将ATP依赖的染色质重塑复合物BAF（哺乳动物SWI/SNF复合物）从含野生型SS18的经典（cBAF）复合物，重定向至含SS18::SSX的非经典（nc）BAF复合物，从而驱动滑膜肉瘤特异性转录程序，最终介导肿瘤发生。小分子靶向治疗的应用边界正突破激酶组范畴，为尚未获批靶向治疗方案的癌症提供了新的治疗工具。本研究证实，SS18::SSX可激活类泛素化（SUMOylation）程序，且SS对小分子SAE1/2抑制剂TAK-981（司布美司他，subasumstat）敏感。机制层面，研究发现TAK-981可使cBAF复合物与多溴相关BAF复合物（PBAF）的成员SMARCE1发生去类泛素化修饰。该修饰的结果是染色质上cBAF复合物的稳定与恢复，使其从由SS18::SSX主导的ncBAF复合物驱动的转录组中脱离。这一表型转变伴随DNA损伤与细胞死亡，最终在人类及小鼠滑膜肉瘤肿瘤模型中均实现了肿瘤抑制。进一步研究显示，TAK-981与标准护理化疗联合使用时，可通过增强DNA损伤程度产生协同抗肿瘤活性，进而诱导肿瘤消退。靶向类泛素化通路可恢复cBAF复合物的正常功能，阻断SS18::SSX介导的ncBAF转录组，从而明确了SS的治疗易感靶点，并将临床在研药物TAK-981定位为治疗此类难治性癌症的新型候选药物。本研究针对SYO.1及SYO.1滑膜肉瘤细胞系中SS18::SSX、SMARCA4、KDM2B及H3K27ac靶标开展了染色质免疫沉淀测序（ChIP-seq）实验。