A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia.
A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia.
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DOI：
10.1158/2159-8290.cd-18-0140
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发表时间：
2018-12
期刊：
影响因子：
28.2
通讯作者：
Savona MR
中科院分区：
文献类型：
--
作者：
Ramsey HE;Fischer MA;Lee T;Gorska AE;Arrate MP;Fuller L;Boyd KL;Strickland SA;Sensintaffar J;Hogdal LJ;Ayers GD;Olejniczak ET;Fesik SW;Savona MR
通过抗凋亡BCL 2家族成员的表达抑制凋亡是急性成髓细胞白血病（AML）的标志。诱导性髓性白血病细胞分化蛋白（MCL-1）是一种抗凋亡BCL-2家族成员，通常在AML细胞中上调，并且通常是对BCL-2抑制剂维奈托克治疗耐药的主要模式。在这里，我们描述了VU 661013，一种新型的，有效的，选择性的MCL-1抑制剂，去稳定BIM/MCL-1协会，导致AML细胞凋亡，并在维奈托克耐药细胞和患者来源的异种移植物中具有活性。此外，VU 661013与维奈托克在AML小鼠模型中安全地联合使用以产生协同作用。重要的是，患者样品的BH 3谱分析和离体药物敏感性测试准确地预测了对MCL-1或BCL-2的选择性抑制剂的细胞应答，并显示了组合的益处。综上所述，这些数据表明，在AML临床试验中合理使用BCL-2和MCL-1抑制剂的顺序或组合的策略。
Suppression of apoptosis by expression of anti-apoptotic BCL2-family members is a hallmark of acute myeloblastic leukemia (AML). Induced myeloid leukemia cell differentiation protein (MCL-1), an anti-apoptotic BCL-2 family member, is commonly upregulated in AML cells, and is often a primary mode of resistance to treatment with the BCL-2 inhibitor, venetoclax. Here, we describe VU661013, a novel, potent, selective MCL-1 inhibitor that de-stabilizes BIM/MCL-1 association, leads to apoptosis in AML, and is active in venetoclax-resistant cells and patient derived xenografts. In addition, VU661013 was safely combined with venetoclax for synergy in murine models of AML. Importantly, BH3 profiling of patient samples, and drug sensitivity testing ex vivo accurately predicted cellular responses to selective inhibitors of MCL-1 or BCL-2, and showed benefit of the combination. Taken together, these data suggest a strategy of rationally employing BCL-2 and MCL-1 inhibitors in sequence or in combination in AML clinical trials.