Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo
Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo
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DOI：
10.1182/blood-2015-04-640920
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发表时间：
2016-03-03
期刊：
影响因子：
20.3
通讯作者：
Hernandez-Ilizaliturri, Francisco J.
中科院分区：
文献类型：
--
作者：
Czuczman, Natalie M.;Barth, Matthew J.;Hernandez-Ilizaliturri, Francisco J.
套细胞淋巴瘤（MCL）的特点是一个积极的临床过程和不可避免的发展难治性疾病，强调需要开发替代的治疗策略。为此，我们在一组MCL细胞系、原代MCL肿瘤细胞和2种不同的人MCL小鼠模型中评价了pevonedistat（MLN 4924），这是一种新型强效和选择性NEDD 8激活酶抑制剂。Pevonedistat暴露导致大多数检测的MCL细胞系和原发性肿瘤细胞发生剂量、时间和半胱天冬酶依赖性细胞死亡。值得关注的是，在半数最大抑制浓度较低（0.1-0.5 μ M）的MCL细胞系中，pevonedistat诱导G1期细胞周期停滞、Bcl-xL水平下调、核因子（NF）-κ B活性降低和细胞凋亡。此外，当与阿糖胞苷、苯达莫司汀或利妥昔单抗联合用药时，pevonedistat表现出累加/协同效应。在体内，与对照组相比，pevonedistat单药治疗延长了2种荷MCL小鼠模型的生存期。与利妥昔单抗或pevonedistat单药治疗相比，Pevonedistat与利妥昔单抗联合治疗可改善生存期。我们的数据表明，pevonedistat在MCL临床前模型中具有显著活性，可能与对NF-κ B活性、Bcl-xL下调和G1细胞周期阻滞的影响相关。我们的研究结果支持进一步研究pevonedistat联合或不联合利妥昔单抗治疗MCL。
Mantle cell lymphoma(MCL) is characterized by an aggressive clinical course and inevitable development of refractory disease, stressing the need to develop alternative therapeutic strategies. To this end, we evaluated pevonedistat (MLN4924), a novel potent and selective NEDD8-activating enzyme inhibitor in a panel of MCL cell lines, primary MCL tumor cells, and 2 distinct murine models of human MCL. Pevonedistat exposure resulted in a dose-, time-, and caspase-dependent cell death in the majority of the MCL cell lines and primary tumor cells tested. Of interest, in the MCL cell lines with lower half-maximal inhibitory concentration (0.1-0.5 mu M), pevonedistat induced G1-phase cell cycle arrest, down-regulation of Bcl-xL levels, decreased nuclear factor (NF)-kappa B activity, and apoptosis. In addition, pevonedistat exhibited additive/synergistic effects when combined with cytarabine, bendamustine, or rituximab. In vivo, as a single agent, pevonedistat prolonged the survival of 2 MCL-bearing mouse models when compared with controls. Pevonedistat in combination with rituximab led to improved survival compared with rituximab or pevonedistat monotherapy. Our data suggest that pevonedistat has significant activity in MCL preclinical models, possibly related to effects on NF-kappa B activity, Bcl-xL downregulation, and G1 cell cycle arrest. Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL.