Boehringer Ingelheim RCV GmbH & Co KG, A-1120 Vienna, Austria.
Boehringer Ingelheim RCV GmbH & Co KG, A-1120 Vienna, Austria.
Cancer Lett. 2018 May 1;421:112-120. doi: 10.1016/j.canlet.2018.02.018. Epub 2018 Feb 14.
Interactions between a new potent Bromodomain and extraterminal domain (BET) inhibitor BI 894999 and the polo-like kinase (PLK) inhibitor volasertib were studied in acute myeloid leukemia cell lines in vitro and in vivo. We provide data for the distinct mechanisms of action of these two compounds with a potential utility in AML based on gene expression, cell cycle profile and modulation of PD biomarkers such as MYC and HEXIM1. In contrast to BI 894999, volasertib treatment neither affects MYC nor HEXIM1 expression, but augments and prolongs the decrease of MYC expression caused by BI 894999 treatment. In vitro combination of both compounds leads to a decrease in S-Phase and to increased apoptosis. In vitro scheduling experiments guided in vivo experiments in disseminated AML mouse models. Co-administration of BI 894999 and volasertib dramatically reduces tumor burden accompanied by long-term survival of tumor-bearing mice and eradication of AML cells in mouse bone marrow. Together, these preclinical findings provide evidence for the strong synergistic effect of BI 894999 and volasertib, warranting future clinical studies in patients with AML to investigate this paradigm.
在体外和体内急性髓细胞白血病细胞系中研究了新型强效溴结构域和末端外结构域（BET）抑制剂 BI 894999 与 Polo 样激酶（PLK）抑制剂 volasertib 之间的相互作用。我们提供了这两种化合物的不同作用机制的数据，这些数据基于基因表达、细胞周期特征以及 PD 生物标志物（如 MYC 和 HEXIM1）的调节，这些标志物在 AML 中具有潜在的应用价值。与 BI 894999 相反，volasertib 治疗既不影响 MYC 也不影响 HEXIM1 的表达，但增强和延长了 BI 894999 治疗引起的 MYC 表达下降。两种化合物的体外联合作用导致 S 期减少，并增加细胞凋亡。体外调度实验指导了弥漫性 AML 小鼠模型中的体内实验。BI 894999 和 volasertib 的联合给药大大降低了肿瘤负担，同时伴有荷瘤小鼠的长期生存和小鼠骨髓中 AML 细胞的消除。这些临床前发现共同为 BI 894999 和 volasertib 的强烈协同作用提供了证据，值得在 AML 患者中进行未来的临床研究来探索这一模式。
