Synovial sarcoma (SS), a rare subtype of soft-tissue sarcoma distinguished by expression of the fusion gene SS18-SSX, predominantly affects the extremities of young patients. Existing anticancer drugs have limited efficacy against this malignancy, necessitating the development of innovative therapeutic approaches. Given the established role of SS18-SSX in epigenetic regulation, we focused on bromodomain and extra-terminal domain protein (BET) inhibitors and epigenetic agents. Our investigation of the BET inhibitor ABBV-075 revealed its pronounced antitumor effects, inducing G1-phase cell-cycle arrest and apoptosis, in four SS cell lines. Notably, BET inhibitors exhibited regulatory control over crucial cell-cycle regulators, such as MYC, p21, CDK4, and CDK6. Additionally, RNA sequencing findings across the four cell lines revealed the significance of fluctuating BCL2 family protein expression during apoptotic induction. Notably, variations in the expression ratio of the anti-apoptotic factor BCLxL and the pro-apoptotic factor BIM may underlie susceptibility to ABBV-075. Additionally, knockdown of SS18-SSX, which upregulates BCL2, reduced the sensitivity to ABBV-075. These findings suggest the potential utility of BET inhibitors targeting the SS18-SSX-regulated intrinsic apoptotic pathway as a promising therapeutic strategy for SS.
滑膜肉瘤（SS）是一种罕见的软组织肉瘤亚型，以表达融合基因SS18-SSX为特征，主要累及年轻患者的四肢。现有抗癌药物对该恶性肿瘤疗效有限，亟需开发创新治疗方法。鉴于SS18-SSX在表观遗传调控中的明确作用，我们聚焦于溴结构域和末端外结构域蛋白（BET）抑制剂及表观遗传药物。通过对BET抑制剂ABBV-075的研究，我们在四种SS细胞系中观察到其显著的抗肿瘤效应，可诱导G1期细胞周期阻滞和细胞凋亡。值得注意的是，BET抑制剂对MYC、p21、CDK4和CDK6等关键细胞周期调节因子具有调控作用。此外，四种细胞系的RNA测序结果显示，BCL2家族蛋白表达水平的波动在凋亡诱导过程中具有重要意义。特别值得注意的是，抗凋亡因子BCLxL与促凋亡因子BIM表达比例的变化可能是影响ABBV-075敏感性的潜在机制。同时，敲除可上调BCL2表达的SS18-SSX基因会降低对ABBV-075的敏感性。这些发现表明，靶向SS18-SSX调控的内源性凋亡通路的BET抑制剂，有望成为治疗滑膜肉瘤的潜在策略。
Therapeutic Potential of Bromodomain and Extra-Terminal Domain Inhibitors for Synovial Sarcoma Cells
肿瘤(癌症)患者之家