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Therapeutic targeting the oncogenic driver EWSR1::FLI1 in Ewing sarcoma through inhibition of the FACT complex

Oncogene volume 42, pages 11–25 (2023)Cite this article

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Abstract

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.

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Fig. 1: The FACT complex is a potential therapeutic target for EwS treatment.
Fig. 2: Verification of in vitro and in vivo tumor-dependency of the FACT complex in EwS.
Fig. 3: The FACT inhibitor CBL0137 suppresses growth of EwS preclinical models in vitro and in vivo.
Fig. 4: The FACT inhibitor CBL0137 suppresses SSRP1 and EWSR1::FLI1 associated oncogenic transcriptional programs.
Fig. 5: The FACT complex and EWSR1::FLI1 form positive feedback loop via mutual transcriptional regulation and activation.
Fig. 6: The FACT complex and EWSR1::FLI1 co-regulate cell cycle/DNA replication process and IGF1R-PI3K-AKT-mTOR pathway in EwS.

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Data availability

RNAseq raw data are accessible at the NCBI Gene Expression Omnibus (GEO) accession code GSE195803 and GSE195804. ChIPseq raw data are accessible at the accession code GSE195802.

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Acknowledgements

This work was supported by Chinese Universities Scientific Fund, Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20212700), National Natural Science Foundation of China (81772655, 81972646 to YT, 82002978 to JM), Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, the Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-01-E00036, China), the Recruitment Program of Global Experts of China (YT), Postdoctoral Science Foundation of China (2019M651527 to JM), and National Research Center for Translational Medicine, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (Open research program to YT). We thank Jing Xue (Shanghai Renji Hospital) and Bing Li (Shanghai Jiao Tong University School of Medicine) for reagents and/or helpful suggestions.

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  1. These authors contributed equally: Jialin Mo, Kezhe Tan, Yu Dong, Wenjie Lu.

Authors and Affiliations

  1. 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

    Jialin Mo, Fang Liu, Yanqing Mei, Kewen Zhao & Yujie Tang

  2. Shanghai Key Laboratory of Reproductive Medicine, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China

    Jialin Mo, Wenjie Lu & Yujie Tang

  3. Department of General Surgery, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, 200062, Shanghai, China

    Kezhe Tan & Zhibao Lv

  4. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Yu Dong & Youqiong Ye

  5. Department of Hepatic Surgery and Liver Transplantation Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200127, Shanghai, China

    Hongting Huang

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Contributions

JM: Conceptualization, project administration, funding acquisition, methodology, investigation, writing (original draft and review and editing) and visualization. KT: Investigation, writing (original draft and review and editing) and visualization. YD: Software, writing (original draft) and visualization. WL: Investigation and visualization. FL: Investigation. YM: Investigation. WL: Investigation. HH: Investigation. KZ: Investigation. ZL: Conceptualization, funding acquisition, resources, supervision. YY: Conceptualization, software, methodology and visualization. YT: Conceptualization, formal analysis, project administration, funding acquisition, resources, supervision, writing (original draft and review and editing) and visualization.

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Correspondence to Zhibao Lv, Youqiong Ye or Yujie Tang.

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Mo, J., Tan, K., Dong, Y. et al. Therapeutic targeting the oncogenic driver EWSR1::FLI1 in Ewing sarcoma through inhibition of the FACT complex. Oncogene 42, 11–25 (2023). https://doi.org/10.1038/s41388-022-02533-1

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