Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL
Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL
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DOI：
10.1182/blood-2018-08-872465
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发表时间：
2019-01-03
期刊：
影响因子：
20.3
通讯作者：
Shipp, Margaret A.
中科院分区：
文献类型：
--
作者：
Bojarczuk, Kamil;Wienand, Kirsty;Shipp, Margaret A.
抑制 B 细胞受体 (BCR) 信号通路是多种 B 细胞恶性肿瘤的一种有前途的治疗策略。然而，BCR 阻断在弥漫性大 B 细胞淋巴瘤 (DLBCL) 中的作用仍不清楚。我们最近对原发性 DLBCL 亚群进行了表征，这些亚群具有扰乱 BCR/磷酸肌醇 3 激酶 (PI3K) 信号传导和失调的 B 细胞淋巴瘤 2 (BCL-2) 表达的独特遗传基础。在此，我们在一组功能和遗传特征 DLBCL 细胞系模型中探讨了 PI3K 抑制剂和 BCL-2 阻断的活性。具有主要 α/δ 活性的 PI3K 抑制剂 wcopanlisib 在所有 BCR 依赖性 DLBCL 中表现出最高的细胞毒性。 copanlisib 的促凋亡作用与 BCL-2 家族成员的 DLBCL 亚型特异性表达失调相关，包括 harakiri (HRK) 及其抗凋亡伙伴 BCL 特大 (BCL-xL)、BCL2 相关蛋白 A1、骨髓细胞白血病 1 (MCL-1) 和细胞死亡的 BCL2 相互作用介质。使用功能性 BH3 分析，我们发现 copanlisib 的细胞毒活性主要通过 BCL-xL 和 MCL-1 依赖性机制介导，可能补充 BCL-2 阻断。出于这些原因，我们评估了 Venetoclax 在 DLBCL 中的单药活性，并鉴定了尽管具有 BCL-2 失调的遗传基础，但对 BCL-2 阻断敏感性有限的亚群。由于这些主要是 BCR 依赖性 DLBCL，我们假设 PI3K α/δ 和 BCL-2 的联合抑制会扰乱 BCR 依赖性和 BCL-2 介导的生存途径。事实上，我们在体外观察到了 Copanlisib/venetoclax 在 BCR 依赖性 DLBCL 中的协同活性，并具有 BCL-2 失调的遗传基础，并在异种移植模型中证实了这些发现。这些结果为 PI3K α/δ 和 BCL-2 阻断在基因定义的 DLBCL 中的合理组合提供了临床前证据。
Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models. A PI3K inhibitor with predominant alpha/delta activity, wcopanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. The proapoptotic effect of copanlisib was associated with DLBCL subtype-specific dysregulated expression of BCL-2 family members including harakiri (HRK) and its antiapoptotic partner BCL extra large (BCL-xL), BCL2 related protein A1, myeloid cell leukemia 1 (MCL-1), and BCL2 interacting mediator of cell death. Using functional BH3 profiling, we found that the cytotoxic activity of copanlisib was primarily mediated through BCL-xL and MCL-1-dependent mechanisms that might complement BCL-2 blockade. For these reasons, we evaluated single-agent activity of venetoclax in the DLBCLs and identified a subset with limited sensitivity to BCL-2 blockade despite having genetic bases of BCL-2 dysregulation. As these were largely BCR-dependent DLBCLs, we hypothesized that combined inhibition of PI3K alpha/delta and BCL-2 would perturb BCR-dependent and BCL-2-mediated survival pathways. Indeed, we observed synergistic activity of copanlisib/venetoclax in BCR-dependent DLBCLs with genetic bases for BCL-2 dysregulation in vitro and confirmed these findings in a xenograftmodel. These results provide preclinical evidence for the rational combination of PI3K alpha/delta and BCL-2 blockade in genetically defined DLBCLs.