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.

中文翻译：

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P300/CBP 的药理学靶向揭示了 EWS：：FLI1 介导的尤文肉瘤衰老逃逸


尤文肉瘤 （ES） 由于难以靶向其主要致癌驱动因素 EWS：：FLI1，因此带来了重大的治疗挑战。我们表明，通过抑制 P300/CBP 靶向 EWS：：FLI1 转录复合物可驱动类似于直接敲低 EWS：：FLI1 的整体转录结果，并进一步产生 ES 患者预后的预后危险因素。我们发现 EWS：：FLI1 通过 ES 细胞和 EWS：：FLI1 允许的间充质干细胞中的重复 GGAA 基序识别和乙酰化编码上调 LMNB1，当被 P300 抑制逆转时，导致 ES 细胞衰老。然后可以通过靶向 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表明了未来治疗探索的一种有吸引力的协同策略。