Mo Jialin, Tan Kezhe, Dong Yu, Lu Wenjie, Liu Fang, Mei Yanqing, Huang Hongting, Zhao Kewen, Lv Zhibao, Ye Youqiong, Tang Yujie
Research Center of Translational medicine, Shanghai children's hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
Shanghai Key Laboratory of Reproductive Medicine, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
Oncogene. 2023 Jan;42(1):11-25. doi: 10.1038/s41388-022-02533-1. Epub 2022 Nov 10.
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.
EWS/ETS融合转录因子，最常见的是EWSR1::FLI1，驱动尤因肉瘤（EwS）的起始和进展。尽管直接靶向EWSR1::FLI1是一项艰巨的挑战，但表观遗传/转录调节剂已被证明是间接破坏其表达和/或功能的有前景的治疗靶点。在这里，我们确定结构特异性识别蛋白1（SSRP1），即促进染色质转录（FACT）复合体的一个亚基，是EwS中由EWSR1::FLI1直接诱导的一个必需的肿瘤依赖性基因。靶向FACT的药物CBL0137在体外和体内对多种EwS临床前模型均表现出强大的治疗效果。从机制上讲，SSRP1和EWSR1::FLI1通过相互转录调控和激活形成致癌正反馈回路，并协同促进细胞周期/DNA复制过程以及IGF1R-PI3K-AKT-mTOR通路以驱动EwS肿瘤发生。FACT抑制剂药物CBL0137有效地靶向EWSR1::FLI1-FACT回路，导致EWSR1::FLI1、SSRP1及其下游效应致癌特征的转录破坏。我们的研究阐明了FACT复合体在促进EWSR1::FLI1的表达和功能中的关键作用，并证明FACT抑制是一种针对EwS的新型有效表观遗传/转录靶向治疗策略，为将EwS纳入CBL0137未来的临床试验提供了临床前支持。
