Zhang Congyi, Yao Yikai, Qian Qiuting, Han Xiongyu, Lu Yunkun, Jiang Xinyi, Cheng Hongqiang, Zhang Xue, Chi Ying, Ke Yuehai, Xiao Peng
Department of Pathology and Pathophysiology, and Department of Respiratory Medicine at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Zhejiang University-University of Edinburgh Joint Institute, ZJU Haining International Campus, Jiaxing, China.
Sci Rep. 2025 May 30;15(1):18978. doi: 10.1038/s41598-025-04153-7.
:ABL1-targeting tyrosine kinase inhibitors (TKIs) dominate the treatment of chronic myeloid leukemia (CML) over the past decades. In this study, we reported an unexpected role of neddylation inhibitors in desensitizing the therapeutic efficacy of BCR::ABL1-targeting TKIs in CML. Unlike their function in reducing drug resistance in many solid tumors, we revealed that neddylation inhibitors counteracted the cytotoxicity of TKIs against CML cells, both in cellular experiments and in animal model. Conversely, neddylation agonist sensitized the function of TKIs. RNA sequencing data revealed that neddylation inhibitor reversed the transcriptomic changes induced by TKI. Co-immunoprecipitation (co-IP) assay identified ABL1 kinase domain as a novel substrate for neddylation. Furthermore, an artificial intelligence (AI) 3-Dimensional spatial structure binding technology was employed to predict the impact of neddylation on the structure of ABL1 kinase domain. Finally, we provided potential evidence showing that TKI therapy decreased the expression of neddylation enzymes in the bone marrow of CML patients. Hence, our study offers new insights into the post-translational modification (PTM)-mediated drug resistance, and highlights the potential clinical benefits of neddylation agonists in improving the responsiveness of BCR::ABL1 TKIs in CML.
在过去几十年中，靶向BCR::ABL1的酪氨酸激酶抑制剂（TKIs）一直主导着慢性髓性白血病（CML）的治疗。在本研究中，我们报告了泛素化抑制剂在使CML中靶向BCR::ABL1的TKIs治疗效果脱敏方面的意外作用。与它们在降低许多实体瘤耐药性中的功能不同，我们发现泛素化抑制剂在细胞实验和动物模型中均抵消了TKIs对CML细胞的细胞毒性。相反，泛素化激动剂增强了TKIs的功能。RNA测序数据显示，泛素化抑制剂逆转了TKI诱导的转录组变化。免疫共沉淀（co-IP）分析确定ABL1激酶结构域是泛素化的新底物。此外，采用人工智能（AI）三维空间结构结合技术预测泛素化对ABL1激酶结构域结构的影响。最后，我们提供了潜在证据表明TKI治疗降低了CML患者骨髓中泛素化酶的表达。因此，我们的研究为翻译后修饰（PTM）介导的耐药性提供了新的见解，并突出了泛素化激动剂在提高CML中BCR::ABL1 TKIs反应性方面的潜在临床益处。
