尤文肉瘤 (ES) 由于难以靶向其主要肿瘤驱动因子 EWS::FLI1，因此带来了重大的治疗挑战。我们表明，通过抑制 P300/CBP 来对 EWS::FLI1 转录复合物进行药理学靶向可驱动与直接敲低 EWS::FLI1 类似的整体转录结果，并进一步产生 ES 患者结果的预后风险因素。我们发现 EWS::FLI1 在 ES 细胞和 EWS::FLI1 允许的间充质干细胞中通过重复的 GGAA 基序识别和乙酰化编码上调 LMNB1，当 P300 抑制逆转时，会导致 ES 细胞衰老。然后可以通过针对 PI3K 信号通路的 senolytics 消除 P300 抑制的衰老 ES 细胞。 ES 细胞对这种联合疗法的脆弱性为未来的治疗探索提供了一种有吸引力的协同策略。© 2024。作者。

Ewing sarcoma (ES) poses a significant therapeutic challenge due to the difficulty in targeting its main oncodriver, EWS::FLI1. We show that pharmacological targeting of the EWS::FLI1 transcriptional complex via inhibition of P300/CBP drives a global transcriptional outcome similar to direct knockdown of EWS::FLI1, and furthermore yields prognostic risk factors for ES patient outcome. We find that EWS::FLI1 upregulates LMNB1 via repetitive GGAA motif recognition and acetylation codes in ES cells and EWS::FLI1-permissive mesenchymal stem cells, which when reversed by P300 inhibition leads to senescence of ES cells. P300-inhibited senescent ES cells can then be eliminated by senolytics targeting the PI3K signaling pathway. The vulnerability of ES cells to this combination therapy suggests an appealing synergistic strategy for future therapeutic exploration.© 2024. The Author(s).