对多发性骨髓瘤（MM）生物学的更好理解已经促使新疗法的开发。然而，MM仍然是一种无法治愈的疾病，需要新的药理策略。Dinaciclib是一种多个细胞周期蛋白依赖激酶（CDK）抑制剂，能够抑制CDK1、2、5和9。在第II期临床试验中，Dinaciclib显示出显著的抗骨髓瘤活性。在本研究中，我们探讨了Dinaciclib诱导的死亡机制，并评估了其与不同BH3模拟剂在MM细胞系以及MM患者浆细胞中的协同作用。我们的结果表明，基于Dinaciclib的与B细胞淋巴瘤2（BCL-2）或B细胞淋巴瘤额外大（BCL-XL）抑制剂的组合显示出协同作用，特别是对于部分依赖髓样细胞白血病序列1（MCL-1）的MM细胞系。与Dinaciclib同时治疗的BH3模拟剂ABT-199或A-1155463在来自MM患者的浆细胞中还显示出协同作用。MM细胞遗传学的改变不会影响Dinaciclib的体外反应，无论单独使用还是与其他治疗联合使用，这表明这些联合疗法可能适用于携带遗传学变异和预后不良的患者。这项研究还打开了在过表达或高度依赖MCL-1的MM患者中，探索细胞周期蛋白依赖激酶9（CDK9）抑制作为一种靶向治疗的可能性。本文受版权保护，版权所有。

A better understanding of multiple myeloma (MM) biology has led to the development of novel therapies. However, MM is still an incurable disease and new pharmacological strategies are needed. Dinaciclib, a multiple cyclin-dependent kinase (CDK) inhibitor, which inhibits CDK1, 2, 5 and 9, displays significant anti-myeloma activity as found in Phase II clinical trials. In the present work, we have explored the mechanism of dinaciclib-induced death and evaluated its enhancement by different BH3 mimetics in MM cell lines as well as in plasma cells from MM patients. Our results indicate a synergistic effect of dinaciclib-based combinations with B-cell lymphoma 2 (BCL-2) or B-cell lymphoma extra-large (BCL-XL ) inhibitors, especially in MM cell lines with partial dependence on myeloid cell leukemia sequence 1 (MCL-1). Simultaneous treatment with dinaciclib and BH3 mimetics ABT-199 or A-1155463 additionally showed a synergistic effect in plasma cells from MM patients, ex vivo. Altered MM cytogenetics did not affect dinaciclib response ex vivo, alone or in combined treatment, suggesting that these combinations could be a suitable therapeutic option for patients bearing cytogenetic alterations and poor prognosis. This work also opens the possibility to explore cyclin-dependent kinase 9 (CDK9) inhibition as a targeted therapy in MM patients overexpressing or with high dependence on MCL-1.This article is protected by copyright. All rights reserved.