Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies
Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies
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DOI：
10.1182/bloodadvances.2019000359
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发表时间：
2020-02-11
期刊：
影响因子：
7.5
通讯作者：
Savona, Michael R.
中科院分区：
文献类型：
--
作者：
Fischer, Melissa A.;Friedlander, Sharon Y.;Savona, Michael R.
选择性核输出抑制剂（SINE）化合物selinexor（KPT-330）和eltanexor（KPT-8602）来自一类靶向输出蛋白-1（XPO 1 [CRM 1]）的新型小分子，XPO 1是一种重要的核质转运蛋白，负责主要肿瘤抑制蛋白和生长调节因子（如p53、p21和p27）的核输出。XPO 1还通过阻断翻译起始因子eIF 4 E的输出来影响关键癌基因（包括MYC、BCL 2、MCL 1和BCL 6）的信使RNA的翻译。维奈托克（ABT-199）是一种有效的、选择性的BCL 2抑制剂，其早期试验显示了对多种血液恶性肿瘤的反应。然而，许多肿瘤对venetoclax没有反应。我们使用急性髓性白血病（AML）和弥漫性大B细胞淋巴瘤（DLBCL）模型，以确定体外和体内对维奈托克和SINE化合物联合治疗的反应。用维奈托克和SINE化合物共处理证明在多个细胞系中丧失活力。进一步的体外分析表明，这种增强的细胞死亡是细胞凋亡增加的结果，导致甲基纤维素测定中克隆形成性的丧失，与p53的活化和MCL 1的丧失一致。用SINE化合物和维奈托克组合治疗导致AML和DLBCL异种移植物中的肿瘤生长减少。组织切片的免疫组织化学分析显示，肿瘤细胞的减少部分是诱导细胞凋亡的结果。在原代AML和DLBCL患者细胞中验证了该组合的增强效果。我们的研究揭示了SINE化合物和维奈托克在侵袭性恶性血液病中的协同作用，并为在临床试验中采用这种方法提供了依据。
The selective inhibitor of nuclear export (SINE) compounds selinexor (KPT-330) and eltanexor (KPT-8602) are from a novel class of small molecules that target exportin-1 (XPO1 [CRM1]), an essential nucleo-cytoplasmic transport protein responsible for the nuclear export of major tumor suppressor proteins and growth regulators such as p53, p21, and p27. XPO1 also affects the translation of messenger RNAs for critical oncogenes, including MYC, BCL2, MCL1, and BCL6, by blocking the export of the translation initiation factor eIF4E. Early trials with venetoclax (ABT-199), a potent, selective inhibitor of BCL2, have revealed responses across a variety of hematologic malignancies. However, many tumors are not responsive to venetoclax. We used models of acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) to determine in vitro and in vivo responses to treatment with venetoclax and SINE compounds combined. Cotreatment with venetoclax and SINE compounds demonstrated loss of viability in multiple cell lines. Further in vitro analyses showed that this enhanced cell death was the result of an increase in apoptosis that led to a loss of clonogenicity in methylcellulose assays, coinciding with activation of p53 and loss of MCL1. Treatment with SINE compounds and venetoclax combined led to a reduction in tumor growth in both AML and DLBCL xenografts. Immunohistochemical analysis of tissue sections revealed that the reduction in tumor cells was partly the result of an induction of apoptosis. The enhanced effects of this combination were validated in primary AML and DLBCL patient cells. Our studies reveal synergy with SINE compounds and venetoclax in aggressive hematologic malignancies and provide a rationale for pursuing this approach in a clinical trial.