Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Ludwig Boltzmann Institute for Hematology & Oncology, Medical University of Vienna, Austria.
Children's Cancer Research Institute (CCRI), Vienna, Austria.
EBioMedicine. 2019 Dec;50:111-121. doi: 10.1016/j.ebiom.2019.11.004. Epub 2019 Nov 21.
Ponatinib is the only approved tyrosine kinase inhibitor (TKI) suppressing BCR-ABL1-mutated cells in chronic myeloid leukemia (CML). However, due to side effects and resistance, BCR-ABL1-mutated CML remains a clinical challenge. Hydroxyurea (HU) has been used for cytoreduction in CML for decades. We found that HU suppresses or even eliminates BCR-ABL1+ sub-clones in heavily pretreated CML patients. Based on this observation, we investigated the effects of HU on TKI-resistant CML cells in vitro.
Viability, apoptosis and proliferation of drug-exposed primary CML cells and BCR-ABL1+ cell lines were examined by flow cytometry and H-thymidine-uptake. Expression of drug targets was analyzed by qPCR and Western blotting.
HU was more effective in inhibiting the proliferation of leukemic cells harboring BCR-ABL1 or T315I-including compound-mutations compared to cells expressing wildtype BCR-ABL1. Moreover, HU synergized with ponatinib and ABL001 in inducing growth inhibition in CML cells. Furthermore, HU blocked cell cycle progression in leukemic cells, which was accompanied by decreased expression of CDK4 and CDK6. Palbociclib, a more specific CDK4/CDK6-inhibitor, was also found to suppress proliferation in primary CML cells and to synergize with ponatinib in producing growth inhibition in BCR-ABL1+ cells, suggesting that suppression of CDK4/CDK6 may be a promising concept to overcome BCR-ABL1-associated TKI resistance.
HU and the CDK4/CDK6-blocker palbociclib inhibit growth of CML clones expressing BCR-ABL1 or complex T315I-including compound-mutations. Clinical studies are required to confirm single drug effects and the efficacy of `ponatinib+HU´ and ´ponatinib+palbociclib´ combinations in advanced CML.
This project was supported by the Austrian Science Funds (FWF) projects F4701-B20, F4704-B20 and P30625.
波那替尼是唯一一种能抑制慢性髓性白血病（CML）中 BCR-ABL1 突变细胞的酪氨酸激酶抑制剂（TKI）。然而，由于副作用和耐药性，BCR-ABL1 突变的 CML 仍然是一个临床挑战。羟基脲（HU）几十年来一直被用于 CML 的细胞减少。我们发现 HU 可抑制甚至消除重度预处理的 CML 患者中的 BCR-ABL1+亚克隆。基于这一观察结果，我们研究了 HU 对体外 TKI 耐药性 CML 细胞的影响。
通过流式细胞术和 H-胸苷摄取检测药物暴露的原代 CML 细胞和 BCR-ABL1+细胞系的活力、凋亡和增殖。通过 qPCR 和 Western blot 分析药物靶点的表达。
HU 对携带 BCR-ABL1 或包含 T315I 复合突变的白血病细胞的增殖抑制作用比对表达野生型 BCR-ABL1 的细胞更有效。此外，HU 与 ponatinib 和 ABL001 协同诱导 CML 细胞生长抑制。此外，HU 阻断白血病细胞的细胞周期进程，伴随 CDK4 和 CDK6 表达降低。更特异的 CDK4/CDK6 抑制剂 palbociclib 也被发现可抑制原代 CML 细胞的增殖，并与 ponatinib 协同作用抑制 BCR-ABL1+细胞的生长抑制，表明抑制 CDK4/CDK6 可能是克服 BCR-ABL1 相关 TKI 耐药的一个有前途的概念。
HU 和 CDK4/CDK6 抑制剂 palbociclib 抑制表达 BCR-ABL1 或复杂 T315I 包含复合突变的 CML 克隆的生长。需要进行临床研究以确认单药作用以及 ponatinib+HU 和 ponatinib+palbociclib 联合治疗晚期 CML 的疗效。
本项目由奥地利科学基金（FWF）项目 F4701-B20、F4704-B20 和 P30625 资助。
Zotero 插件
