Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response
Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response
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DOI：
10.1182/blood-2017-04-779447
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发表时间：
2017-08-10
期刊：
影响因子：
20.3
通讯作者：
Levine, Ross L.
中科院分区：
文献类型：
--
作者：
Amatangelo, Michael D.;Quek, Lynn;Levine, Ross L.
异柠檬酸脱氢酶2（IDH 2）中R140和R172的复发性突变发生在许多癌症中，包括12%的急性髓性白血病（AML）。在临床前模型中，这些突变导致致癌代谢物R-2-羟基戊二酸（2-HG）的积累，并诱导造血分化阻滞。单药enasidenib（AG-221/CC-90007）是一种选择性突变IDH 2（mIDH 2）抑制剂，在1期试验中，复发性/难治性AML（rrAML）患者的mIDH 2总缓解率为40.3%。然而，其作用机制和与反应相关的生物标志物仍不清楚。在此，我们测量了来自临床试验的连续患者样本中的2-HG、mIDH 2等位基因负荷和共发生的体细胞突变，并将其与临床反应相关联。此外，我们使用流式细胞术来评估mIDH 2对造血分化的抑制。我们在R140和R172 mIDH 2AML亚型中观察到有效的2-HG抑制，具有不同的动力学，其先于临床反应。单独抑制2-HG不能预测反应，因为大多数无反应的患者也表现出2-HG抑制。观察到完全缓解（CR）伴mIDH 2持续存在以及造血干细胞和祖细胞区室正常化伴功能性mIDH 2中性粒细胞出现。在CR患者的一个子集中，mIDH 2等位基因负荷降低，并且在缓解时仍然检测不到。NRAS和其他MAPK通路效应子中的共发突变在无应答患者中富集，与RAS信号传导导致原发性治疗耐药一致。总之，这些数据支持分化是复发性/难治性AML患者中enasidenib疗效的主要机制，并提供了对耐药机制的深入了解，为未来基于机制的联合治疗研究提供信息。
Recurrent mutations at R140 and R172 in isocitrate dehydrogenase 2 (IDH2) occur in many cancers, including similar to 12% of acute myeloid leukemia (AML). In preclinical models these mutations cause accumulation of the oncogenic metabolite R-2-hydroxyglutarate (2-HG) and induce hematopoietic differentiation block. Single-agent enasidenib (AG-221/CC-90007), a selective mutant IDH2 (mIDH2) inhibitor, produced an overall response rate of 40.3% in relapsed/refractory AML (rrAML) patients with mIDH2 in a phase 1 trial. However, its mechanism of action and biomarkers associated with response remain unclear. Here, we measured 2-HG, mIDH2 allele burden, and co-occurring somatic mutations in sequential patient samples from the clinical trial and correlated these with clinical response. Furthermore, we used flow cytometry to assess inhibition of mIDH2 on hematopoietic differentiation. We observed potent 2-HG suppression in both R140 and R172mIDH2AML subtypes, with different kinetics, which preceded clinical response. Suppression of 2-HG alone did not predict response, because most nonresponding patients also exhibited 2-HG suppression. Complete remission (CR) with persistence of mIDH2 and normalization of hematopoietic stem and progenitor compartments with emergence of functional mIDH2 neutrophils were observed. In a subset of CR patients, mIDH2 allele burden was reduced and remained undetectable with response. Co-occurring mutations in NRAS and other MAPK pathway effectors were enriched in nonresponding patients, consistent with RAS signaling contributing to primary therapeutic resistance. Together, these data support differentiation as the main mechanism of enasidenib efficacy in relapsed/refractory AML patients and provide insight into resistance mechanisms to inform future mechanism-based combination treatment studies.