Luo Chen-Hui, Hu Li-Hong, Liu Jie-Yang, Xia Li, Zhou Li, Sun Ren-Hong, Lin Chen-Cen, Qiu Xing, Jiang Biao, Yang Meng-Ying, Zhang Xue-Hong, Yang Xiao-Bao, Chen Guo-Qiang, Lu Ying
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.
Institute of Dermatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Nat Commun. 2024 Dec 5;15(1):10594. doi: 10.1038/s41467-024-54354-3.
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.
皮肤T细胞淋巴瘤（CTCL）是一种起源于皮肤并侵犯全身造血系统的异质性非霍奇金淋巴瘤。目前的治疗方法，包括化疗和单克隆抗体，疗效有限且副作用发生率高，这凸显了靶向治疗的必要性。通过小抑制剂文库进行筛选，我们在此确定细胞周期蛋白依赖性激酶9（CDK9）是CTCL生长的驱动因素。单细胞RNA测序分析揭示了一个具有独特活跃增殖特征的CDK9恶性T细胞簇。靶向CDK9的抑制、耗竭或蛋白酶体靶向嵌合体（PROTAC）介导的降解在体外和小鼠模型中均显著降低CTCL细胞的生长。CDK9还通过招募E3连接酶HUWE1促进维甲酸受体α（RARα）的降解。CDK9-PROTAC（GT-02897）与全反式维甲酸（ATRA）联合给药在体外和异种移植模型中导致肿瘤生长的协同减弱，为彻底根除CTCL提供了一种潜在的转化治疗方法。
