{"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":"<p><p>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.</p>","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}
引用次数: 0
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.
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.
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