Department of Medicine, Clinic III-Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany.
Int J Mol Sci. 2023 Jan 10;24(2):1359. doi: 10.3390/ijms24021359.
Numerous hematologic neoplasms, including acute B-lymphoblastic leukemia (B-ALL), are characterized by overexpression of anti-apoptotic BCL-2 family proteins. Despite the high clinical efficacy of the specific BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), dose limitation and resistance argue for the early exploration of rational combination strategies. Recent data indicated that BCL-2 inhibition in B-ALL with rearrangements is a promising intervention option; however, combinatorial approaches have not been in focus so far. The PI3K/AKT pathway has emerged as a possible target structure due to multiple interactions with the apoptosis cascade as well as relevant dysregulation in B-ALL. Herein, we demonstrate for the first time that combined BCL-2 and PI3K/AKT inhibition has synergistic anti-proliferative effects on B-ALL cell lines. Of note, all tested combinations (venetoclax + PI3K inhibitors idelalisib or BKM-120, as well as AKT inhibitors MK-2206 or perifosine) achieved comparable anti-leukemic effects. In a detailed analysis of apoptotic processes, among the PI3K/AKT inhibitors only perifosine resulted in an increased rate of apoptotic cells. Furthermore, the combination of venetoclax and perifosine synergistically enhanced the activity of the intrinsic apoptosis pathway. Subsequent gene expression studies identified the pro-apoptotic gene as a possible player in synergistic action. All combinatorial approaches additionally modulated extrinsic apoptosis pathway genes. The present study provides rational combination strategies involving selective BCL-2 and PI3K/AKT inhibition in B-ALL cell lines. Furthermore, we identified a potential mechanistic background of the synergistic activity of combined venetoclax and perifosine application.
许多血液系统恶性肿瘤，包括急性 B 淋巴细胞白血病（B-ALL），其特征是抗凋亡 BCL-2 家族蛋白的过度表达。尽管特异性 BCL-2 抑制剂 venetoclax 在急性髓细胞白血病（AML）和慢性淋巴细胞白血病（CLL）中的临床疗效很高，但剂量限制和耐药性要求早期探索合理的联合策略。最近的数据表明，BCL-2 抑制在伴有重排的 B-ALL 中是一种有前途的干预选择；然而，迄今为止，联合方法还不是重点。PI3K/AKT 通路由于与凋亡级联的多种相互作用以及 B-ALL 中的相关失调，已成为一个可能的靶结构。在此，我们首次证明联合 BCL-2 和 PI3K/AKT 抑制对 B-ALL 细胞系具有协同的抗增殖作用。值得注意的是，所有测试的组合（venetoclax + PI3K 抑制剂 idelalisib 或 BKM-120 以及 AKT 抑制剂 MK-2206 或 perifosine）都实现了相当的抗白血病作用。在对凋亡过程的详细分析中，在 PI3K/AKT 抑制剂中，只有 perifosine 导致凋亡细胞的比率增加。此外，venetoclax 和 perifosine 的组合协同增强了内在凋亡途径的活性。随后的基因表达研究确定了促凋亡基因 作为协同作用的可能参与者。所有组合方法还另外调节了外在凋亡途径基因。本研究为 B-ALL 细胞系中涉及选择性 BCL-2 和 PI3K/AKT 抑制的合理联合策略提供了依据。此外，我们确定了联合 venetoclax 和 perifosine 应用协同作用的潜在机制背景。
