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

Chen-Hui Luo, Li-Hong Hu, Jie-Yang Liu, Li Xia, Li Zhou, Ren-Hong Sun, Chen-Cen Lin, Xing Qiu, Biao Jiang, Meng-Ying Yang (), Xue-Hong Zhang (), Xiao-Bao Yang (), Guo-Qiang Chen () and Ying Lu ()
Additional contact information
Chen-Hui Luo: Shanghai Jiao Tong University School of Medicine
Li-Hong Hu: Shanghai Jiao Tong University
Jie-Yang Liu: Shanghai Jiao Tong University
Li Xia: Shanghai Jiao Tong University School of Medicine
Li Zhou: Shanghai Jiao Tong University School of Medicine
Ren-Hong Sun: Gluetacs Therapeutics (Shanghai) Co., Ltd.
Chen-Cen Lin: ShanghaiTech University
Xing Qiu: ShanghaiTech University
Biao Jiang: ShanghaiTech University
Meng-Ying Yang: Shanghai Jiao Tong University
Xue-Hong Zhang: Dalian Medical University
Xiao-Bao Yang: Gluetacs Therapeutics (Shanghai) Co., Ltd.
Guo-Qiang Chen: Shanghai Jiao Tong University School of Medicine
Ying Lu: Shanghai Jiao Tong University

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-54354-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54354-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-54354-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().