慢性淋巴细胞白血病bcl2抑制剂耐药的认识与靶向

IF 2.7 3区医学 Q2 HEMATOLOGY

Hematology-Oncology Clinics of North America Pub Date : 2025-07-22 DOI:10.1016/j.hoc.2025.06.001

Alexander F Vom Stein, Lukas P Frenzel

{"title":"慢性淋巴细胞白血病bcl2抑制剂耐药的认识与靶向","authors":"Alexander F Vom Stein, Lukas P Frenzel","doi":"10.1016/j.hoc.2025.06.001","DOIUrl":null,"url":null,"abstract":"Chronic lymphocytic leukemia (CLL) treatment has evolved with the introduction of venetoclax, a selective BCL-2 inhibitor capable of inducing apoptosis in CLL cells. However, resistance has emerged as a significant clinical obstacle. Here, we delineate the multifactorial basis of venetoclax resistance in CLL by exploring genetic mutations, epigenetic alterations, microenvironmental protection, metabolic rewiring, and downstream signaling adaptations. Furthermore, we examine strategies to overcome resistance, including drug combinations, next-generation BCL-2 inhibitors, and novel immunotherapeutic approaches. Finally, we consider the clinical implications of emerging resistance patterns and discuss future directions in a personalized therapy.","PeriodicalId":55060,"journal":{"name":"Hematology-Oncology Clinics of North America","volume":" ","pages":""},"PeriodicalIF":2.7000,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Understanding and Targeting BCL2-inhibitor Resistance in Chronic Lymphocytic Leukemia.\",\"authors\":\"Alexander F Vom Stein, Lukas P Frenzel\",\"doi\":\"10.1016/j.hoc.2025.06.001\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Chronic lymphocytic leukemia (CLL) treatment has evolved with the introduction of venetoclax, a selective BCL-2 inhibitor capable of inducing apoptosis in CLL cells. However, resistance has emerged as a significant clinical obstacle. Here, we delineate the multifactorial basis of venetoclax resistance in CLL by exploring genetic mutations, epigenetic alterations, microenvironmental protection, metabolic rewiring, and downstream signaling adaptations. Furthermore, we examine strategies to overcome resistance, including drug combinations, next-generation BCL-2 inhibitors, and novel immunotherapeutic approaches. Finally, we consider the clinical implications of emerging resistance patterns and discuss future directions in a personalized therapy.\",\"PeriodicalId\":55060,\"journal\":{\"name\":\"Hematology-Oncology Clinics of North America\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2025-07-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Hematology-Oncology Clinics of North America\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.hoc.2025.06.001\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hematology-Oncology Clinics of North America","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.hoc.2025.06.001","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"HEMATOLOGY","Score":null,"Total":0}

引用次数: 0

摘要

慢性淋巴细胞白血病（CLL）的治疗随着venetoclax的引入而发展，venetoclax是一种选择性的BCL-2抑制剂，能够诱导CLL细胞凋亡。然而，耐药性已成为一个重要的临床障碍。在这里，我们通过探索基因突变、表观遗传改变、微环境保护、代谢重布线和下游信号适应，描绘了CLL中venetoclax耐药的多因素基础。此外，我们研究了克服耐药性的策略，包括药物联合、下一代BCL-2抑制剂和新的免疫治疗方法。最后，我们考虑了新出现的耐药模式的临床意义，并讨论了个性化治疗的未来方向。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Understanding and Targeting BCL2-inhibitor Resistance in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) treatment has evolved with the introduction of venetoclax, a selective BCL-2 inhibitor capable of inducing apoptosis in CLL cells. However, resistance has emerged as a significant clinical obstacle. Here, we delineate the multifactorial basis of venetoclax resistance in CLL by exploring genetic mutations, epigenetic alterations, microenvironmental protection, metabolic rewiring, and downstream signaling adaptations. Furthermore, we examine strategies to overcome resistance, including drug combinations, next-generation BCL-2 inhibitors, and novel immunotherapeutic approaches. Finally, we consider the clinical implications of emerging resistance patterns and discuss future directions in a personalized therapy.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Hematology-Oncology Clinics of North America 医学-血液学

CiteScore

4.10

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Hematology/Oncology Clinics updates you on the latest trends in patient management, keeps you up to date on the newest advances, and provides a sound basis for choosing treatment options. Under the direction of an experienced guest editor, each issue focuses on a single topic in hematology and oncology, including hemostasis and thrombosis, molecular and cellular basis of hematology, coagulation disorders, and cancers—bone, gastrointestinal, head and neck, lymphomas, neuroendocrine, breast, renal cell, melanoma, and more.