<br>CDK4/6 和 XPO1 的双重抑制可诱导衰老，并对基于 CRBN 的 PROTAC 药物产生后天脆弱性,Gastroenterology

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CDK4/6 和 XPO1 的双重抑制可诱导衰老，并对基于 CRBN 的 PROTAC 药物产生后天脆弱性
Gastroenterology ( IF 25.7 ) Pub Date : 2024-01-21 , DOI: 10.1053/j.gastro.2024.01.025
Hui Wang ₁ , Shengxian Yuan ₂ , Quan Zheng ₃ , Sisi Zhang ₁ , Qianqian Zhang ₄ , Shuyi Ji ₅ , Wei Wang ₁ , Ying Cao ₁ , Yuchen Guo ₁ , Xupeng Yang ₅ , Haigang Geng ₆ , Fan Yang ₇ , Shuijun Xi ₅ , Guangzhi Jin ₈ , Jianming Zhang ₉ , Qiang Gao ₅ , René Bernards ₁₀ , Wenxin Qin ₁ , Cun Wang ₁

Affiliation

State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
National Research Center for Translational Medicine (Shanghai), State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China.
Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Pharmacy, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Interventional Radiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Institute of Translational Medicine, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China.
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands.

尽管肝癌的治疗选择越来越多，但只有一小部分患者获得长期临床获益。在这里，我们的目标是开发肝癌的新治疗方法。进行了化合物筛选，以确定与细胞周期蛋白依赖性激酶 (CDK) 4/6 抑制剂联合使用时可以协同诱导衰老的抑制剂。在一组人类肝癌细胞系和多种肝癌模型中研究了 CDK4/6 抑制剂和输出蛋白 1 (XPO1) 抑制剂对细胞衰老的联合作用。进行了衰老药物筛选，以确定选择性杀死衰老肝癌细胞的药物。 CDK4/6抑制剂和XPO1抑制剂的组合在体外和体内协同诱导肝癌细胞衰老。 XPO1 抑制剂通过引起 RB1 在细胞核中积累而发挥作用，导致 E2F 信号传导减少并促进 CDK4/6 抑制剂诱导衰老。通过衰老药物筛选，基于 cereblon (CRBN) 的蛋白水解靶向嵌合体 (PROTAC) ARV-825 被确定为一种可以选择性杀死衰老肝癌细胞的药物。 CRBN 的上调是衰老肝癌细胞的一个弱点，使其对基于 CRBN 的 PROTAC 药物敏感。从机制上讲，我们发现泛素特异性肽酶 2 (USP2) 直接与 CRBN 相互作用，导致衰老肝癌细胞中 CRBN 的去泛素化和稳定化。我们的研究表明，通过 CDK4/6 抑制剂和 XPO1 抑制剂的组合，在诱导肝癌细胞衰老方面具有显着的协同作用。这些发现还揭示了衰老肝癌细胞对基于 CRBN 的 PROTAC 疗法的脆弱性的分子过程。

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Dual Inhibition of CDK4/6 and XPO1 Induces Senescence With Acquired Vulnerability to CRBN-Based PROTAC Drugs

Despite the increasing number of treatment options available for liver cancer, only a small proportion of patients achieve long-term clinical benefits. Here, we aim to develop new therapeutic approaches for liver cancer. A compound screen was conducted to identify inhibitors that could synergistically induce senescence when combined with cyclin-dependent kinase (CDK) 4/6 inhibitor. The combination effects of CDK4/6 inhibitor and exportin 1 (XPO1) inhibitor on cellular senescence were investigated in a panel of human liver cancer cell lines and multiple liver cancer models. A senolytic drug screen was performed to identify drugs that selectively killed senescent liver cancer cells. The combination of CDK4/6 inhibitor and XPO1 inhibitor synergistically induces senescence of liver cancer cells in vitro and in vivo. The XPO1 inhibitor acts by causing accumulation of RB1 in the nucleus, leading to decreased E2F signaling and promoting senescence induction by the CDK4/6 inhibitor. Through a senolytic drug screen, cereblon (CRBN)–based proteolysis targeting chimera (PROTAC) ARV-825 was identified as an agent that can selectively kill senescent liver cancer cells. Up-regulation of CRBN was a vulnerability of senescent liver cancer cells, making them sensitive to CRBN-based PROTAC drugs. Mechanistically, we find that ubiquitin specific peptidase 2 (USP2) directly interacts with CRBN, leading to the deubiquitination and stabilization of CRBN in senescent liver cancer cells. Our study demonstrates a striking synergy in senescence induction of liver cancer cells through the combination of CDK4/6 inhibitor and XPO1 inhibitor. These findings also shed light on the molecular processes underlying the vulnerability of senescent liver cancer cells to CRBN-based PROTAC therapy.

更新日期：2024-01-21

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