Zielonka Klaudia, Jamroziak Krzysztof
Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Poland.
Doctoral School, Medical University of Warsaw, Poland.
Adv Clin Exp Med. 2024 Dec;33(12):1421-1433. doi: 10.17219/acem/181145.
Venetoclax, a BH3 mimetic, is a novel targeted anti-cancer drug with a unique mechanism of action leading to the execution of apoptosis through inhibition of the Bcl-2 protein. The development of venetoclax has revolutionized the treatment paradigm of several hematologic malignancies, including treatment-naïve and relapsed or refractory chronic lymphocytic leukemia (CLL) as well as acute myeloid leukemia (AML) in unfit patients. However, despite the high effectiveness of venetoclax in these diseases, some patients, as in the case with other targeted therapies, develop primary or secondary resistance to the drug. Various mechanisms contributing to the resistance to venetoclax have been elucidated, including selection of mutations in the BCL-2 binding groove which decrease affinity to venetoclax, or compensatory overexpression of anti-apoptotic proteins such as MCL-1. Moreover, alterations in cell metabolism and signaling pathways like MAPK or ERK activation have also been reported, suggesting the resistance to venetoclax is highly complex and involves multiple pathways. This review aimed to describe the mechanisms of resistance to venetoclax in AML, CLL, multiple myeloma, and other hematologic malignancies, as well as to propose a perspective to circumvent it.
维奈克拉是一种BH3模拟物，是一种新型靶向抗癌药物，其作用机制独特，可通过抑制Bcl-2蛋白来诱导细胞凋亡。维奈克拉的研发彻底改变了几种血液系统恶性肿瘤的治疗模式，包括初治以及复发或难治性慢性淋巴细胞白血病（CLL），还有不适宜接受常规治疗的急性髓系白血病（AML）患者。然而，尽管维奈克拉在这些疾病中疗效显著，但与其他靶向治疗一样，部分患者会对该药物产生原发性或继发性耐药。目前已阐明了多种导致对维奈克拉耐药的机制，包括在BCL-2结合凹槽中选择降低对维奈克拉亲和力的突变，或抗凋亡蛋白如MCL-1的代偿性过表达。此外，也有报道称细胞代谢以及MAPK或ERK激活等信号通路发生改变，这表明对维奈克拉的耐药性非常复杂，涉及多条途径。本综述旨在描述AML、CLL、多发性骨髓瘤和其他血液系统恶性肿瘤中对维奈克拉耐药的机制，并提出克服耐药性的策略。
