Selective strong synergism of Ruxolitinib and second generation tyrosine kinase inhibitors to overcome bone marrow stroma related drug resistance in chronic myelogenous leukemia
Selective strong synergism of Ruxolitinib and second generation tyrosine kinase inhibitors to overcome bone marrow stroma related drug resistance in chronic myelogenous leukemia
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DOI：
10.1016/j.leukres.2013.11.006
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发表时间：
2014-02-01
影响因子：
2.7
通讯作者：
Pane, Fabrizio
中科院分区：
文献类型：
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作者：
Quintarelli, Concetta;De Angelis, Biagio;Pane, Fabrizio
BCR-ABL+ 1（562）细胞株在BM间充质细胞产生的基质条件培养基中培养时，TKIs的IC50显著升高。特别是，虽然基质共培养中的伊马替尼IC50远高于药物的体内通过水平，但第二代TKIs的IC50仍低于其通过水平。此外，我们提供了第一代和第二代TKI与JAK抑制剂Ruxolitinib之间的协同作用的正式比较，以克服BM基质相关的TKI耐药。综上所述，我们的数据为TKIs和Ruxolitinib联合治疗提供了理论依据，目的是根除BM壁龛中的原发性BCR-ABL+细胞。(C) 2013 Elsevier Ltd.版权所有。
The IC50 of TKIs is significantly increased when BCR-ABL+ 1(562 cell line is cultured in stroma conditioned media produced by BM mesenchymal cells. In particular, while the Imatinib IC50 in the stromal cocultures was well above the in vivo through levels of the drug, the IC5Os of second generation TKIs were still below their through levels. Moreover, we provide a formal comparison of the synergy between first and second generation TKIs with the JAK inhibitor Ruxolitinib to overcome BM stroma related TKI resistance. Taken together, our data provide a rationale for the therapeutic combination of TKIs and Ruxolitinib with the aim to eradicate primary BCR-ABL+ cells homed in BM niches. (C) 2013 Elsevier Ltd. All rights reserved.