Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance.
Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance.
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DOI：
10.1158/1535-7163.mct-08-0314
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发表时间：
2008-10
影响因子：
5.7
通讯作者：
Hazlehurst LA
中科院分区：
文献类型：
--
作者：
Bewry NN;Nair RR;Emmons MF;Boulware D;Pinilla-Ibarz J;Hazlehurst LA
甲磺酸伊马替尼是一种针对致癌酪氨酸激酶BCR-ABL的有效的分子靶向治疗方法。尽管甲磺酸伊马替尼对慢性粒细胞白血病(CML)有相当的疗效，但晚期CML患者往往对这种药物无效。骨髓是慢性粒细胞白血病的主要微环境，含有丰富的可溶性因子和细胞外基质，可能影响药物的疗效。为了研究骨髓微环境对甲磺酸伊马替尼敏感性的影响，我们使用了体外共培养的骨髓基质模型。我们的数据显示，在骨髓基质来源的条件培养液(CM)中培养K562细胞足以导致对bcr-abl抑制剂的耐药性。耐药与pTyrStat3的增加有关，而pTyrStat5的增加没有注意到。此外，耐药性与STAT3靶基因Bcl-xl、Mcl-1和Survivin水平的增加有关。最后，用小干扰RNA降低STAT3水平可使培养在CM中的K562细胞对甲磺酸伊马替尼诱导的细胞死亡敏感。重要的是，STAT3依赖是在CM中生长的细胞所特有的，因为在常规生长条件下降低STAT3水平对甲磺酸伊马替尼的敏感性没有影响。总之，这些数据支持非bcr-abl依赖的甲磺酸伊马替尼耐药的新机制，并为在骨髓微环境中使用STAT3抑制剂来提高甲磺酸伊马替尼的疗效提供了临床前理论依据。
Imatinib mesylate is a potent, molecularly targeted therapy against the oncogenic tyrosine kinase BCR-ABL. Although imatinib mesylate has considerable efficacy against chronic myeloid leukemia (CML), advanced-stage CML patients frequently become refractory to this agent. The bone marrow is the predominant microenvironment of CML and is a rich source of both soluble factors and extracellular matrices, which may influence drug response. To address the influence of the bone marrow microenvironment on imatinib mesylate sensitivity, we used an in vitro coculture bone marrow stroma model. Our data show culturing K562 cells, in bone marrow stroma-derived conditioned medium (CM), is sufficient to cause resistance to BCR-ABL inhibitors. Drug resistance correlated with increased pTyrStat3, whereas no increases in pTyrStat5 were noted. Moreover, resistance was associated with increased levels of the Stat3 target genes Bcl-xl, Mcl-1, and survivin. Finally, reducing Stat3 levels with small interfering RNA sensitized K562 cells cultured in CM to imatinib mesylate-induced cell death. Importantly, Stat3 dependency was specific for cells grown in CM, as reducing Stat3 levels in regular growth conditions had no effect on imatinib mesylate sensitivity. Together, these data support a novel mechanism of BCR-ABL-independent imatinib mesylate resistance and provide preclinical rationale for using Stat3 inhibitors to increase the efficacy of imatinib mesylate within the context of the bone marrow microenvironment.