Targeting IDH Mutations in AML: Wielding the Double-edged Sword of Differentiation

doi:10.2174/1568009620666200424145622
摘要

通过DNA测序对急性髓系白血病(AML)的基因组特征进行了阐明，这种疾病具有明显的驱动突变，可能对靶向治疗有反应。大约15-23%的AML基因组存在异柠檬酸脱氢酶两种异构体(IDH1或IDH2)中的一种突变。这些酶是基本细胞代谢的组成介质，但它们的突变形式在癌症中合成一种异常代谢物，2-羟基戊二酸，反过来作为一种多基因调节酶的竞争性抑制剂。因此，白血病的IDH突变导致基因组结构和基因活性的改变，最终导致正常骨髓分化的停止。这些发现激发了一类新的选择性小分子的发展，这些小分子有能力抑制突变的IDH酶，同时保留正常的细胞代谢。这些药物在动物模型和早期临床试验中显示出良好的抗白血病活性，目前正进入第三期研究。这篇综述将聚焦于日益增多的评估IDH抑制剂治疗IDH突变AML的临床前和临床数据。这些数据表明诱导细胞分化是IDH抑制剂临床疗效的核心机制，同时也介导了IDH分化综合征患者的毒性。目前正在进行IDH抑制剂联合其他AML治疗的疗效研究，以评估潜在的协同组合，并在现有的标准护理方案中确定IDH抑制剂的合适位置。
关键词: 急性髓系白血病，异柠檬酸脱氢酶，IDH1，IDH2，ivosidenib，enasidenib
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DOI https://dx.doi.org/10.2174/1568009620666200424145622	Print ISSN 1568-0096
Publisher Name Bentham Science Publisher	Online ISSN 1873-5576
当代肿瘤药物靶点

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当代肿瘤药物靶点

针对AML中的IDH突变：挥舞着差异化的双刃剑

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