CDK9 Recruits HUWE1 to Degrade RARα and Offers Therapeutic Opportunities for Cutaneous T-cell Lymphoma

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Dec 5

PMID 39632829

Authors

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

Ying Lu

Affiliations

Soon will be listed here.

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 CDK9 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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