2. Academic Validation
  3. CDK9 recruits HUWE1 to degrade RARα and offers therapeutic opportunities for cutaneous T-cell lymphoma

CDK9 recruits HUWE1 to degrade RARα and offers therapeutic opportunities for cutaneous T-cell lymphoma

  • Nat Commun. 2024 Dec 5;15(1):10594. doi: 10.1038/s41467-024-54354-3.
Chen-Hui Luo # 1 2,  Li-Hong Hu # 2,  Jie-Yang Liu # 2,  Li Xia # 3,  Li Zhou 3,  Ren-Hong Sun 4,  Chen-Cen Lin 5,  Xing Qiu 5,  Biao Jiang 5,  Meng-Ying Yang 6,  Xue-Hong Zhang 7,  Xiao-Bao Yang 8,  Guo-Qiang Chen 9 10 11,  Ying Lu 12
Affiliations

Affiliations

  • 1 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Institute of Dermatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 3 Department of Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Gluetacs Therapeutics (Shanghai) Co., Ltd., Shanghai, China.
  • 5 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.
  • 6 Institute of Dermatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. ymy@shsmu.edu.cn.
  • 7 Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. zhangxuehong1984@163.com.
  • 8 Gluetacs Therapeutics (Shanghai) Co., Ltd., Shanghai, China. yang.xiaobao@gluetacs.com.
  • 9 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. chengq@shsmu.edu.cn.
  • 10 Institute of Aging & Tissue Regeneration, State Key Laboratory of Systems Medicine for Cancer, Research Units of Stress and Tumor (2019RU043), Chinese Academy of Medical Sciences, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. chengq@shsmu.edu.cn.
  • 11 School of Basic Medicine and Life Science, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China. chengq@shsmu.edu.cn.
  • 12 Institute of Dermatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. stove@shsmu.edu.cn.
  • # Contributed equally.
PMID: 39632829 DOI: 10.1038/s41467-024-54354-3
Abstract

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous non-Hodgkin lymphoma originating in the skin and invading the systemic hematopoietic system. Current treatments, including chemotherapy and monoclonal Antibodies yielded limited responses with high incidence of side effects, highlighting the need for targeted therapy. Screening with small inhibitors library, herein we identify cyclin dependent kinase 9 (CDK9) as a driver of CTCL growth. Single-cell RNA-seq analysis reveals a CDK9high malignant T cell cluster with a unique actively proliferating feature. Inhibition, depletion or proteolysis targeting chimera (PROTAC)-mediated degradation of CDK9 significantly reduces CTCL cell growth in vitro and in murine models. CDK9 also promotes degradation of retinoic acid receptor α (RARα) via recruiting the E3 Ligase HUWE1. Co-administration of CDK9-PROTAC (GT-02897) with all-trans retinoic acid (ATRA) leads to synergistic attenuation of tumor growth in vitro and in xenograft models, providing a potential translational treatment for complete eradication of CTCL.

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