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中华细胞与干细胞杂志(电子版) ›› 2026, Vol. 16 ›› Issue (02) : 86 -93. doi: 10.3877/cma.j.issn.2095-1221.2026.02.003

综述

肿瘤细胞对类泛素化抑制剂MLN4924的耐药机制及其应对措施的研究进展
邢磊1, 卜玉1,2, 张明华3, 范皎1,()   
  1. 1100853 北京,解放军总医院第二医学中心老年医学研究所
    2100853 北京,解放军医学院
    3100853 北京,解放军总医院医疗保障中心
  • 收稿日期:2025-08-31 出版日期:2026-04-01
  • 通信作者: 范皎

Progress in the resistance mechanisms of tumor cells to the neddylation inhibitor MLN4924 and its countermeasures

Lei Xing1, Yu Bu1,2, Minghua Zhang3, Jiao Fan1,()   

  1. 1Institute of Geriatrics, National Clinical Research Center of Geriatrics Disease, Second Medical Center of Chinese PLA General Hospital, Beijing 100853, China
    2Chinese PLA Medical School, Beijing 100853, China
    3Medical Supplies Center of Chinese PLA General Hospital, Beijing 100853, China
  • Received:2025-08-31 Published:2026-04-01
  • Corresponding author: Jiao Fan
引用本文:

邢磊, 卜玉, 张明华, 范皎. 肿瘤细胞对类泛素化抑制剂MLN4924的耐药机制及其应对措施的研究进展[J/OL]. 中华细胞与干细胞杂志(电子版), 2026, 16(02): 86-93.

Lei Xing, Yu Bu, Minghua Zhang, Jiao Fan. Progress in the resistance mechanisms of tumor cells to the neddylation inhibitor MLN4924 and its countermeasures[J/OL]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2026, 16(02): 86-93.

类泛素化过程通过连续的酶级联反应将神经前体细胞表达发育性下调8因子(NEDD8)共价结合到底物蛋白上,影响底物蛋白稳定性、构象和功能等,从而调控下游诸多生物学过程。类泛素化过程与多种类型的肿瘤进展和预后相关。NEDD8激活酶(NAE)作为类泛素化过程中目前已知的唯一活化酶,是开发抗癌药物的重要靶点。MLN4924是一种选择性的NAE抑制剂,对多种类型的实体肿瘤及血液系统肿瘤具有较好的治疗作用,目前已有41项临床试验进入Ⅱ/Ⅲ期,具有较好的应用前景。肿瘤细胞的耐药性是肿瘤患者治疗失败的重要原因。肿瘤细胞一旦获得耐药能力,会影响患者的预后。本文就现阶段对MLN4924耐药机制的研究进展及解决其耐药问题的措施作一综述。

The neddylation process covalently conjugates neural precursor cell expressed developmentally downregulated 8 (NEDD8) to substrate proteins through a continuous enzymatic cascade reaction, which affects the stability, conformation, and function of substrate proteins, thereby regulating numerous downstream biological processes. The neddylation process is associated with the progression and prognosis of various types of tumors. As the only currently known activating enzyme in the neddylation process, NEDD8-activating enzyme (NAE) is an important target for the development of anti-cancer drugs. MLN4924, a selective NAE inhibitor, has good therapeutic effects on various types of solid tumors and hematological malignancies. Currently, 41 clinical trials have entered phases Ⅱ/Ⅲ, indicating promising application prospects. The drug resistance of tumor cells is an important cause of treatment failure in cancer patients. Once tumor cells acquire drug resistance, it will significantly affect the prognosis of patients. This article reviews the current research progress on the resistance mechanism of MLN4924 and the measures to address the problem of resistance to it.

图1 类泛素化过程注:NEDD8为神经的前体细胞表达发育性下调8因子;NAE为NEDD8激活酶;UBC12为泛素结合酶12;Cullin-Ring ligase为Cullin-Ring泛素连接酶
表1 MLN4924相关的临床试验研究
试验编号 涉及药物 治疗疾病 试验分期 治疗效果
NCT01415765 MLN4924/Etoposide/Prednisone/Vincristine/Cyclophosphamide/Doxorubicin/Rituximab 弥漫大B细胞淋巴瘤 Ⅰ期/Ⅱ期 未公布
NCT01011530 MLN4924 黑色素瘤 Ⅰ期 未公布
NCT00677170 MLN4924 非血液系统恶性肿瘤 Ⅰ期 未公布
NCT02122770 MLN4924/Fluconazole/Itraconazole/Docetaxel/Carboplatin/Paclitaxel 晚期实体肿瘤 Ⅰ期 缓解者占比:22.2%
NCT03813147 Azacitidine/Cytarabine/Fludarabine Phosphate/Methotrexate/MLN4924 急性髓系白血病
骨髓增生异常综合征
Ⅰ期 缓解者占比:33.3%
NCT01814826 MLN4924/Azacitidine 急性粒细胞白血病 Ⅰ期 完全缓解:43%
部分缓解:14%
NCT00722488 MLN4924 淋巴瘤/多发性骨髓瘤 Ⅰ期 未公布
NCT00911066 MLN4924/Azacitidine 急性粒细胞白血病
骨髓增生异常综合征
急性淋巴细胞白血病
Ⅰ期 未公布
NCT01862328 MLN4924/Paclitaxel/Gemcitabine/Docetaxel/Carboplatin 实体肿瘤 Ⅰ期 完全缓解:0
部分缓解:19%
NCT03772925 Belinostat/MLN4924 急性髓系白血病
骨髓增生异常综合征
Ⅰ期 未公布
NCT03745352 Azacitidine/MLN4924 急性髓系白血病 Ⅱ期 未公布
NCT03965689 Carboplatin/Paclitaxel/MLN4924 非小细胞肺癌 Ⅱ期 完全缓解:0
部分缓解:16%
NCT03770260 Ixazomib Citrate/MLN4924 多发性骨髓瘤 Ⅰ期 未分析
NCT04800627 Pembrolizumab/MLN4924 晚期实体肿瘤 Ⅰ期/Ⅱ期 未分析
NCT03479268 Ibrutinib/MLN4924 难治性慢性淋巴细胞白血病 Ⅰ期 未公布
NCT03330821 Cytarabine/Idarubicin/MLN4924 急性髓系白血病 Ⅰ期/Ⅱ期 未公布
NCT04172844 Azacitidine/Venetoclax/MLN4924 急性粒细胞白血病 Ⅰ期 未公布
NCT03009240 Decitabine/MLN4924 急性髓系白血病 Ⅰ期 未公布
NCT03323034 Irinotecan/MLN4924/Temozolomide 难治性实体肿瘤或淋巴瘤 Ⅰ期 缓解者占比:16.7%
NCT03862157 Azacitidine/MLN4924/Venetoclax 急性髓系白血病 Ⅰ期/Ⅱ期 未公布
NCT03459859 MLN4924/Cytarabine 骨髓增生异常综合征 Ⅰ期 未公布
NCT03386214 MLN4924/Ruxolitinib 骨髓纤维化 Ⅰ期 未公布
NCT03330106 MLN4924/Docetaxel/Carboplatin/Paclitaxe 晚期实体肿瘤 Ⅰ期 缓解者占比:9.1%
NCT03709576 MLN4924/Azacitidine 急性髓系白血病 Ⅱ期 未分析
NCT02782468 MLN4924/Azacitidine 骨髓增生异常综合征 Ⅰ期 缓解者占比:100%
NCT03486314 MLN4924/Rifampin/Docetaxel/Carboplatin/Paclitaxel 晚期实体肿瘤 Ⅰ期 完全缓解:0
部分缓解:33.3%
NCT03057366 MLN4924/Docetaxel/Carboplatin/Paclitaxel 晚期实体肿瘤 Ⅰ期 缓解者占比:0
NCT03349281 MLN4924/Vincristine/Dexamethasone/PEG-asparaginase/Doxorubicin/Cytarabine/Methotrexate/Hydrocortisone 难治性急性淋巴细胞白血病
非霍奇金淋巴瘤
Ⅰ期 未公布
NCT03814005 Azacitidine/MLN4924 血液系统恶性肿瘤 Ⅰ期 缓解者占比:50%
NCT04266795 MLN4924/Venetoclax/Azacitidine 急性髓系白血病 Ⅱ期 未公布
NCT04175912 Carboplatin/Paclitaxel/MLN4924 肝内胆管癌 Ⅱ期 无治疗效果
NCT03013998 MLN4924 急性髓系白血病 Ⅰ期/Ⅱ期 未公布
NCT04712942 MLN4924/Azacitidine 骨髓增生异常综合征 Ⅱ期 未公布
NCT03319537 MLN4924/Pemetrexed cisplatin 间皮瘤 Ⅰ期/Ⅱ期 缓解者占比:22.2%
NCT04090736 MLN4924/Azacitidine 急性髓系白血病 Ⅲ期 未公布
NCT04985656 MLN4924/Decitabine/Cedazuridine 高危骨髓增生异常综合征 Ⅱ期 未公布
NCT03228186 MLN4924/Docetaxel 晚期非小细胞肺癌 Ⅱ期 缓解者占比:22%
NCT04484363 MLN4924/Azacitidine 骨髓增生异常综合征 未注明 未公布
NCT03268954 Azacitidine/MLN4924 骨髓增生异常综合征 Ⅲ期 缓解者占比:56.3%
NCT02610777 Azacitidine/MLN4924 骨髓增生异常综合征/白血病 Ⅱ期 缓解者占比:71%
NCT03238248 Azacitidine/MLN4924 骨髓增生异常综合征 Ⅱ期 缓解者占比:23.9%
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