Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia
Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia
复制标题
DOI：
10.1158/1078-0432.ccr-16-1930
复制
发表时间：
2017-05-01
影响因子：
11.5
通讯作者：
Loges, Sonja
中科院分区：
文献类型：
--
作者：
Ben-Batalla, Isabel;Erdmann, Robert;Loges, Sonja
目的：BCR-ABL激酶抑制剂已成功用于慢性粒细胞白血病（CML）的治疗。然而，耐药疾病和BCR-ABL 1非依赖性白血病干细胞和祖细胞（LSPC）的持续存在仍然是临床挑战。受体酪氨酸激酶Axl可以介导不同癌细胞的存活和治疗抗性。实验设计：我们使用来自CML患者的原代细胞和TKI敏感和耐药BCR-ABL 1（+）CML细胞系以及新的ponatinib耐药细胞系KCL-22 PonR。我们分析了小分子Axl抑制剂BGB 324在体外和体内对Axl基因和药理学阻断的影响。在BCR-ABL 1-unmutated细胞中，我们还研究了BGB 324与imatinib.Results的组合：我们证明了Axl受体酪氨酸激酶在CML患者的原代细胞中的过表达，与健康个体相比，Axl在BCR-ABL TKI耐药患者中的表达进一步增加。我们发现，Axl阻断可降低BCR-ABL TKI敏感性CML细胞（包括CD 34（+）细胞）的生长，并通过抑制Stat 5活化与伊马替尼产生累加效应。BGB 324还可抑制BCR-ABL TKI耐药细胞，包括T315 I突变和泊那替尼耐药原代细胞。BGB 324在BCR-ABL 1 T315 I突变和泊那替尼耐药的临床前小鼠模型中发挥了治疗作用。值得注意的是，BGB 324不抑制BCR-ABL 1，因此抑制CML独立的BCR-ABL 1突变status.Conclusions：我们的数据表明，Axl抑制BCR-ABL TKI敏感以及耐药CML的治疗潜力，并支持临床试验的需要。(C)2016年AACR。
Purpose: BCR-ABL kinase inhibitors are employed successfully for chronic myeloid leukemia (CML) treatment. However, resistant disease and persistence of BCR-ABL1-independent leukemia stem and progenitor cells (LSPC) remain clinical challenges. The receptor tyrosine kinase Axl can mediate survival and therapy resistance of different cancer cells. We investigated the therapeutic potential of Axl inhibition in CML.Experimental Design: We used primary cells from patients with CML and TKI-sensitive and -resistant BCR-ABL1(+) CML cell lines and a novel ponatinib-resistant cell line KCL-22 PonR. We analyzed the effects of genetic and pharmacologic Axl blockade by the small-molecule Axl inhibitor BGB324 in vitro and in vivo. In BCR-ABL1-unmutated cells, we also investigated BGB324 in combination with imatinib.Results: We demonstrate overexpression of Axl receptor tyrosine kinase in primary cells of patients with CML compared with healthy individuals and a further increase of Axl expression in BCR-ABL TKI-resistant patients. We show that Axl blockage decreased growth of BCR-ABL TKIsensitive CML cells including CD34(+) cells and exerts additive effects with imatinib via inhibition of Stat5 activation. BGB324 also inhibits BCR-ABL TKI-resistant cells, including T315I-mutated and ponatinib-resistant primary cells. BGB324 exerted therapeutic effects in BCR-ABL1 T315Imutated and ponatinib-resistant preclinical mouse models. Notably, BGB324 does not inhibit BCR-ABL1 and consequently inhibits CML independent of BCR-ABL1 mutational status.Conclusions: Our data show that Axl inhibition has therapeutic potential in BCR-ABL TKI-sensitive as well as -resistant CML and support the need for clinical trials. (C) 2016 AACR.