2. Academic Validation
  3. 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

  • Oncogene. 2022 Nov 10. doi: 10.1038/s41388-022-02533-1.
Jialin Mo # 1 2,  Kezhe Tan # 3,  Yu Dong # 4,  Wenjie Lu # 2,  Fang Liu 1,  Yanqing Mei 1,  Hongting Huang 5,  Kewen Zhao 1,  Zhibao Lv 6,  Youqiong Ye 7,  Yujie Tang 8 9
Affiliations

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.
  • 2 Shanghai Key Laboratory of Reproductive Medicine, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
  • 3 Department of General Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, 200062, Shanghai, China.
  • 4 Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 5 Department of Hepatic Surgery and Liver Transplantation Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200127, Shanghai, China.
  • 6 Department of General Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, 200062, Shanghai, China. zhibaolyu@163.com.
  • 7 Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. youqiong.ye@shsmu.edu.cn.
  • 8 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. yujietang@shsmu.edu.cn.
  • 9 Shanghai Key Laboratory of Reproductive Medicine, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China. yujietang@shsmu.edu.cn.
  • # Contributed equally.
PMID: 36357572 DOI: 10.1038/s41388-022-02533-1
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z