Tsubaki Masanobu
Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University.
Yakugaku Zasshi. 2018;138(12):1461-1466. doi: 10.1248/yakushi.18-00142.
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.
对断点簇区域-阿贝尔森（BCR-ABL）酪氨酸激酶抑制剂（TKI）伊马替尼产生耐药性是慢性髓性白血病（CML）治疗中的一个主要问题。伊马替尼耐药通常是由BCR-ABL1中的二次突变引起的。然而，在没有这种突变的情况下，这种不依赖BCR-ABL1的耐药性的基础仍有待阐明。本研究的目的是确定CML中伊马替尼耐药的机制。为了深入了解不依赖BCR-ABL1的伊马替尼耐药机制，我们进行了基于阵列的比较基因组杂交。我们鉴定了各种与耐药相关的基因，重点关注受体酪氨酸激酶MET。用MET抑制剂治疗可使K562/IR细胞对BCR-ABL TKIs重新敏感。在K562/IR细胞中联合使用伊马替尼和MET抑制剂可抑制细胞外信号调节激酶1/2（ERK1/2）和c-Jun氨基末端激酶（JNK）的激活，但不影响AKT的激活。此外，MET抑制剂和伊马替尼的联合使用在体内抑制了肿瘤生长。这些结果表明，MET/ERK和MET/JNK的激活是BCR-ABL TKI耐药的潜在机制。我们的研究结果提供了关于CML中伊马替尼耐药机制的新的重要信息，并揭示了可能参与BCR-ABL TKI耐药的新蛋白。
