Department of Internal Medicine, Jacobi Medical Center, Bronx, NY 10461, USA.
Department of Hematology and Oncology, The University of Texas at San Antonio, San Antonio, TX 78249, USA.
Cells. 2024 Nov 20;13(22):1922. doi: 10.3390/cells13221922.
Overexpression of the anti-apoptotic protein BCL-2 is a key factor in the pathogenesis of chronic lymphocytic leukemia (CLL) and is associated with poor clinical outcomes. Therapeutic activation of apoptosis in cancer cells using the BCL-2 inhibitor (BCL2i) venetoclax has shown remarkable efficacy in clinical trials, both as monotherapy and combination regimens. However, patients with CLL experience a highly variable clinical course, facing significant challenges in advanced stages due to disease relapse and the emergence of resistant clones. Resistance mechanisms include acquired mutations, alteration of pro-apoptotic and anti-apoptotic proteins, metabolic reprogramming, epigenetic changes, and aberrant signaling pathways. To address this complex disease and improve progression-free survival, strategies targeting multiple signaling pathways and mechanisms have been explored. Randomized clinical trials of venetoclax in combination with Bruton tyrosine kinase (BTK) inhibitors or CD20 monoclonal antibodies have significantly outperformed traditional chemoimmunotherapy in both treatment-naïve and relapsed patients, achieving undetectable minimal residual disease (uMRD) and durable remissions. This review explores the intricate balance between BCL-2 family proteins and their role in the intrinsic apoptosis pathway, discusses venetoclax resistance mechanisms, and highlights the evolving role of venetoclax and other BCL2i-based combination therapies in CLL treatment.
抗凋亡蛋白 BCL-2 的过度表达是慢性淋巴细胞白血病 (CLL) 发病机制中的一个关键因素，与不良的临床结局相关。使用 BCL-2 抑制剂 (BCL2i) 维奈托克在癌细胞中诱导凋亡的治疗激活已在临床试验中显示出显著疗效，无论是作为单药治疗还是联合治疗方案。然而，CLL 患者的临床病程高度可变，由于疾病复发和耐药克隆的出现，在晚期面临重大挑战。耐药机制包括获得性突变、促凋亡和抗凋亡蛋白的改变、代谢重编程、表观遗传改变和异常信号通路。为了解决这一复杂疾病并改善无进展生存期，已经探索了靶向多种信号通路和机制的策略。维奈托克联合 Bruton 酪氨酸激酶 (BTK) 抑制剂或 CD20 单克隆抗体的随机临床试验在初治和复发患者中的疗效均明显优于传统的化疗免疫治疗，达到了可检测到的微小残留疾病 (uMRD) 和持久缓解。这篇综述探讨了 BCL-2 家族蛋白之间的复杂平衡及其在内在凋亡途径中的作用，讨论了维奈托克耐药机制，并强调了维奈托克和其他基于 BCL2i 的联合治疗在 CLL 治疗中的不断发展的作用。
