癌症研究
K562细胞
髓系白血病
阿布勒
甲磺酸伊马替尼
酪氨酸激酶
MAPK/ERK通路
伊马替尼
化学
激酶
达沙替尼
白血病
医学
生物
酪氨酸激酶抑制剂
原癌基因酪氨酸蛋白激酶Src
断点群集区域
信号转导
免疫学
内科学
癌症
细胞生物学
受体
出处
期刊:Yakugaku zasshi
[Pharmaceutical Society of Japan]
日期:2018-01-01
被引量:1
标识
DOI:10.1248/yakushi.18-00142
摘要
Resistance to the breakpoint cluster region-abelson (BCR-ABL) tyrosine kinase inhibitor (TKI), imatinib, poses a major problem in the treatment of chronic myeloid leukemia (CML). Imatinib resistance often results from a secondary mutation in BCR-ABL1. However, the basis of this BCR-ABL1-independent resistance in the absence of such mutation remains to be elucidated. The aim of the present study is to identify the mechanism of imatinib resistance in CML. To gain insight into BCR-ABL1-independent imatinib resistance mechanisms, we performed an array-based comparative genomic hybridization. We identified various resistance-related genes, focusing on the receptor tyrosine kinase MET. Treatment with an MET inhibitor resensitized K562/IR cells to BCR-ABL TKIs. A treatment combining imatinib and a MET inhibitor in K562/IR cells inhibited extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) activation, but did not affect AKT activation. Moreover, the combination of MET inhibitor and imatinib suppressed tumor growth in vivo. These results indicate that the activation of MET/ERK and MET/JNK are potential mechanisms of BCR-ABL TKI resistance. Our findings provide new and important information concerning the mechanisms of imatinib resistance in CML, and reveal new proteins potentially involved in BCR-ABL TKI resistance.
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