Lei Hu, Jin Jin, Liu Meng, Li Xiangyun, Luo Hao, Yang Li, Xu Hanzhang, Wu Yingli
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Leuk Res. 2018 Jan;64:17-23. doi: 10.1016/j.leukres.2017.11.007. Epub 2017 Nov 11.
Drug resistance to tyrosine kinase inhibitors (TKIs) is currently a clinical problem of chronic myelogenous leukemia (CML). Bcr-Abl protein depletion is considered as a way to overcome drug resistance to TKIs. In our study, Chk1 inhibitors, AZD7762 and MK-8776, had strong antitumor effects on CML cell line KBM5 and imatinib-resistant form KBM5. Moreover, Chk1 inhibitors showed a strong cytotoxic effect on leukemia cells from primary CML and imatinib-resistance CML patients, but low cytotoxic effect on normal human mononuclear cells. Then, we found that Chk1 inhibitors induced apoptosis and increased DNA damage in CML cell lines with the degradation of the Bcr-Abl protein. Using the proteasome inhibitor and an immunoprecipitation assay, we found that Chk1 inhibitors triggered the degradation of Bcr-Abl through ubiquitination, which is depending on E3 ubiquitin ligase CHIP. At last, MK-8776 showed a significant tumor-suppressive effect of KBM5 cell in xenograft tumor models. Taking together, these findings suggest that targeting Chk1 may overcome TKIs resistance for the treatment of CML.
对酪氨酸激酶抑制剂（TKIs）的耐药性是目前慢性粒细胞白血病（CML）的一个临床问题。Bcr-Abl蛋白的耗竭被认为是克服对TKIs耐药性的一种方法。在我们的研究中，Chk1抑制剂AZD7762和MK-8776对CML细胞系KBM5和伊马替尼耐药形式的KBM5具有强大的抗肿瘤作用。此外，Chk1抑制剂对原发性CML和伊马替尼耐药CML患者的白血病细胞显示出强大的细胞毒性作用，但对正常人单核细胞的细胞毒性作用较低。然后，我们发现Chk1抑制剂在CML细胞系中诱导细胞凋亡并增加DNA损伤，同时伴有Bcr-Abl蛋白的降解。使用蛋白酶体抑制剂和免疫沉淀试验，我们发现Chk1抑制剂通过泛素化触发Bcr-Abl的降解，这依赖于E3泛素连接酶CHIP。最后，MK-8776在异种移植肿瘤模型中对KBM5细胞显示出显著的肿瘤抑制作用。综上所述，这些发现表明靶向Chk1可能克服TKIs耐药性以治疗CML。
