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靶向WEE1：一种新兴的血液系统恶性肿瘤治疗策略(英文)

李浩波¹, Thekra Khushafa¹, 杨超颖¹, 朱黎明², 孙星¹, 聂玲³, 刘静^1,*

¹中南大学湘雅二医院血液科，中南大学生命科学学院分子生物学研究中心，湖南省基础与应用血液学重点实验室，长沙 410083；²湖南省人民医院(湖南师范大学附属第一医院)呼吸与危重症医学科，湖南省呼吸康复临床医学研究中心，长沙 410005；³中南大学湘雅医院血液科，长沙 410008

摘要

血液系统恶性肿瘤，包括白血病、淋巴瘤和多发性骨髓瘤，是一类以癌细胞增殖失控为特征的高危疾病。这类疾病的核心病理机制之一是由遗传和表观遗传异常导致的细胞周期失调。在这一过程中，细胞周期蛋白依赖性激酶(cyclindependentkinase, CDK)与其功能伴侣细胞周期蛋白形成的复合物在细胞周期调控中扮演着关键角色。然而，尽管CDK抑制剂在临床前研究中显示出潜力，但其在临床应用中的转化效果却令人失望。近年来，越来越多的研究揭示了WEE1 G2检查点激酶(WEE1)在调节CDK活性中的重要作用。WEE1通过调控CDK的磷酸化状态影响细胞周期的进程，从而在癌症的发生、发展和预后中发挥关键作用。基于这一发现，多种针对WEE1的治疗抑制剂已被开发并进入临床试验，显示出潜在的临床应用前景。因此，WEE1被认为是一个有望通过调节异常细胞周期来治疗血液系统恶性肿瘤的新靶点。尽管如此，WEE1在血液系统疾病中的具体作用机制仍不明确。在本综述中，我们聚焦血液系统恶性肿瘤，详细描述了WEE1的生物学结构及其在细胞周期调控中的功能，总结了WEE1在癌症发生、进展和预后中的最新研究进展，并探讨了针对WEE1的治疗策略及其在临床中的应用前景，旨在为未来研究WEE1在血液系统恶性肿瘤中的作用提供新的思路和方向。

关键词： 血液系统恶性肿瘤; 细胞周期; 细胞周期蛋白依赖性激酶; WEE1

Targeting WEE1: a rising therapeutic strategy for hematologic malignancies

LI Hao-Bo¹, Thekra Khushafa¹, YANG Chao-Ying¹, ZHU Li-Ming², SUN Xing¹, NIE Ling³, LIU Jing^1,*

¹Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha 410083, China；²Department of Respiratory and Critical Care Medicine, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), China Clinical Medicine Research Center for Respiratory Rehabilitation in Hunan Province, Changsha 410005, China；³Department of Hematology, Xiangya Hospital, Central South University, Changsha 410008, China

Abstract

Hematologic malignancies, including leukemia, lymphoma, and multiple myeloma, are hazardous diseases characterized by the uncontrolled proliferation of cancer cells. Dysregulated cell cycle resulting from genetic and epigenetic abnormalities constitutes one of the central events. Importantly, cyclin-dependent kinases (CDKs), complexed with their functional partner cyclins, play dominating roles in cell cycle control. Yet, efforts in translating CDK inhibitors into clinical benefits have demonstrated disappointing outcomes. Recently, mounting evidence highlights the emerging significance of WEE1 G2 checkpoint kinase (WEE1) to modulate CDK activity, and correspondingly, a variety of therapeutic inhibitors have been developed to achieve clinical benefits. Thus, WEE1 may become a promising target to modulate the abnormal cell cycle. However, its function in hematologic diseases remains poorly elucidated. In this review, focusing on hematologic malignancies, we describe the biological structure of WEE1, emphasize the latest reported function of WEE1 in the carcinogenesis, progression, as well as prognosis, and finally summarize the therapeutic strategies by targeting WEE1.

Key words: hematologic malignancies; cell cycle; cyclin-dependent kinases (CDKs); WEE1

收稿日期：　　录用日期：

通讯作者：刘静　　E-mail:

DOI: 10.13294/j.aps.2025.0058

引用本文：

李浩波, Thekra Khushafa, 杨超颖, 朱黎明, 孙星, 聂玲, 刘静. 靶向WEE1：一种新兴的血液系统恶性肿瘤治疗策略(英文)[J]. 生理学报 2025; 77 (5): 839-854.

LI Hao-Bo, Thekra Khushafa, YANG Chao-Ying, ZHU Li-Ming, SUN Xing, NIE Ling, LIU Jing. Targeting WEE1: a rising therapeutic strategy for hematologic malignancies. Acta Physiol Sin 2025; 77 (5): 839-854