Therapeutic targeting the oncogenic driver EWSR1::FLI1 in Ewing sarcoma through inhibition of the FACT complex
Therapeutic targeting the oncogenic driver EWSR1::FLI1 in Ewing sarcoma through inhibition of the FACT complex
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DOI：
10.1038/s41388-022-02533-1
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发表时间：
2022-11-10
期刊：
影响因子：
8
通讯作者：
Tang, Yujie
中科院分区：
文献类型：
--
作者：
Mo, Jialin;Tan, Kezhe;Tang, Yujie
EWS/ETS融合转录因子，最常见的是EWSR 1：：FLI 1，驱动尤文肉瘤（EwS）的发生和发展。尽管直接靶向EWSR 1：：FLI 1是一个巨大的挑战，但表观遗传/转录调节剂已被证明是间接破坏其表达和/或功能的有前途的治疗靶点。在这里，我们确定了结构特异性识别蛋白1（SSRP 1），促进染色质转录（FACT）复合物的一个亚基，是EWSR 1：：FLI 1在EwS中直接诱导的一个重要的肿瘤依赖性基因。靶向FACT的药物CBL 0137在体外和体内均对多种EwS临床前模型表现出有效的治疗功效。在机制上，SSRP 1和EWSR 1：：FLI 1通过相互转录调控和激活形成致癌正反馈环，协同促进细胞周期/DNA复制过程和IGF 1 R-PI 3 K-AKT-mTOR通路，驱动EwS致癌。FACT抑制剂药物CBL 0137有效靶向EWSR 1：：FLI 1-FACT回路，导致EWSR 1：：FLI 1、SSRP 1及其下游效应子致癌特征的转录破坏。我们的研究说明了FACT复合物在促进EWSR 1：：FLI 1的表达和功能方面的关键作用，并证明了FACT抑制是一种针对EwS的新型有效的表观遗传/转录靶向治疗策略，为将EwS添加到CBL 0137的未来临床试验中提供了临床前支持。
EWS/ETS fusion transcription factors, most commonly EWSR1::FLI1, drives initiation and progression of Ewing sarcoma (EwS). Even though direct targeting EWSR1::FLI1 is a formidable challenge, epigenetic/transcriptional modulators have been proved to be promising therapeutic targets for indirectly disrupting its expression and/or function. Here, we identified structure-specific recognition protein 1 (SSRP1), a subunit of the Facilitates Chromatin Transcription (FACT) complex, to be an essential tumor-dependent gene directly induced by EWSR1::FLI1 in EwS. The FACT-targeted drug CBL0137 exhibits potent therapeutic efficacy against multiple EwS preclinical models both in vitro and in vivo. Mechanistically, SSRP1 and EWSR1::FLI1 form oncogenic positive feedback loop via mutual transcriptional regulation and activation, and cooperatively promote cell cycle/DNA replication process and IGF1R-PI3K-AKT-mTOR pathway to drive EwS oncogenesis. The FACT inhibitor drug CBL0137 effectively targets the EWSR1::FLI1-FACT circuit, resulting in transcriptional disruption of EWSR1::FLI1, SSRP1 and their downstream effector oncogenic signatures. Our study illustrates a crucial role of the FACT complex in facilitating the expression and function of EWSR1::FLI1 and demonstrates FACT inhibition as a novel and effective epigenetic/transcriptional-targeted therapeutic strategy against EwS, providing preclinical support for adding EwS to CBL0137's future clinical trials.