Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition
Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition
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DOI：
10.1158/2159-8290.cd-18-0877
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发表时间：
2018-12-01
期刊：
影响因子：
28.2
通讯作者：
Intlekofer, Andrew M.
中科院分区：
文献类型：
--
作者：
Harding, James J.;Lowery, Maeve A.;Intlekofer, Andrew M.
异柠檬酸脱氢酶（IDH 1或IDH 2）的胞质或线粒体亚型的体细胞突变通过代谢产物2-羟基戊二酸（2 HG）的产生促进肿瘤发生。异构体选择性IDH抑制剂抑制2 HG产生并诱导IDH 1和IDH 2突变型恶性肿瘤患者的临床反应尽管IDH抑制剂的活性很有希望，但对介导IDH抑制抗性的机制知之甚少。在这里，我们描述了四个临床病例，这些病例鉴定了突变型IDH亚型转换，从突变型IDH 1转换为突变型IDH 2，反之亦然，作为实体瘤和液体瘤中对IDH抑制的获得性临床耐药机制。IDH突变型癌症可以通过从突变型IDH 1到突变型IDH 2或反之亦然的“同种型转换”而对同种型选择性IDH抑制产生抗性，从而恢复肿瘤的2 HG产生。这些发现强调了持续产生2 HG在肿瘤进展中的作用，并提出了预防或克服耐药性的治疗策略。(C)2018年AACR。
Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 or IDH2, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with IDH1- and IDH2-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors.SIGNIFICANCE: IDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by "isoform switching" from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2HG production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance. (C) 2018 AACR.