Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells.
Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells.
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DOI：
10.1111/cas.12849
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发表时间：
2016-02
期刊：
影响因子：
5.7
通讯作者：
Kim DK
中科院分区：
文献类型：
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作者：
Naka K;Ishihara K;Jomen Y;Jin CH;Kim DH;Gu YK;Jeong ES;Li S;Krause DS;Kim DW;Bae E;Takihara Y;Hirao A;Oshima H;Oshima M;Ooshima A;Sheen YY;Kim SJ;Kim DK
最近治疗CML患者的策略主要集中在研究酪氨酸激酶抑制剂（TKI）的新组合，以及确定可以根除CML白血病起始细胞（CML‐ LIC）的新型转化研究药物。然而，人们对这种CML‐LIC靶向治疗可能给CML患者带来的治疗益处知之甚少。在这项研究中，我们研究了EW-7197的治疗潜力，EW-7197是一种口服生物可利用的转化生长因子-β信号传导抑制剂，最近被批准为研究性新药（NIH，USA），在体内抑制CML-LIC。与TKI单独给药相比，TKI + EW-7197给药可显著延迟CML感染小鼠的疾病复发并延长生存期。值得注意的是，EW-7197 + TKI联合治疗可有效消除CML-LIC，即使它们表达TKI-耐药T315 I突变BCR-ABL 1癌基因。总的来说，这些结果表明EW-7197可能是一种有希望的候选药物，可以通过与TKI联合使用来根除CML-LIC，从而使CML患者受益匪浅。
Recent strategies for treating CML patients have focused on investigating new combinations of tyrosine kinase inhibitors (TKIs) as well as identifying novel translational research agents that can eradicate CML leukemia‐initiating cells (CML‐LICs). However, little is known about the therapeutic benefits such CML‐LIC targeting therapies might bring to CML patients. In this study, we investigated the therapeutic potential of EW‐7197, an orally bioavailable transforming growth factor‐β signaling inhibitor which has recently been approved as an Investigational New Drug (NIH, USA), to suppress CML‐LICs in vivo. Compared to TKI treatment alone, administration of TKI plus EW‐7197 to CML‐affected mice significantly delayed disease relapse and prolonged survival. Notably, combined treatment with EW‐7197 plus TKI was effective in eliminating CML‐LICs even if they expressed the TKI‐resistant T315I mutant BCR‐ABL1 oncogene. Collectively, these results indicate that EW‐7197 may be a promising candidate for a new therapeutic that can greatly benefit CML patients by working in combination with TKIs to eradicate CML‐LICs.