Efficacy of MEK inhibition in patients with histiocytic neoplasms
Efficacy of MEK inhibition in patients with histiocytic neoplasms
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DOI：
10.1038/s41586-019-1012-y
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发表时间：
2019-03-28
期刊：
影响因子：
64.8
通讯作者：
Hyman, David M.
中科院分区：
文献类型：
--
作者：
Diamond, Eli L.;Durham, Benjamin H.;Hyman, David M.
组织细胞肿瘤是一组克隆性造血疾病，以丝裂原活化蛋白激酶(MAPK)途径(1，2)的不同突变为标志。对于50%具有BRAF(V600)突变(3-5)的组织细胞增多症患者，抑制RAF是非常有效的，并显著改变了疾病的自然病史(6，7)。然而，对于其余50%缺乏BRAF(V600)突变的患者，还没有标准的治疗方法。尽管ERK依赖被认为是组织细胞肿瘤的一致特征，但这一点仍未在临床上得到证实，在缺乏BRAF(V600)突变的患者中发现的许多激酶突变以前没有生物学特征。在这里，我们通过组织细胞增多症患者口服MEK1和MEK2的抑制剂cobimetinib的概念验证临床试验，展示了ERK在组织细胞增多症中的依赖性。患者被纳入研究，而不考虑他们的肿瘤基因。同时，在接受治疗的患者中发现的MAPK变化的特征是他们激活ERK的能力。在我们治疗的18例患者中，总有效率为%(90%可信区间73-100)。反应是持久的，到目前为止没有获得性抵抗力。在一年中，100%的反应是持续的，94%的患者保持无进展。Cobimetinib治疗是有效的，无论是哪种基因，在ARAF、BRAF、RAF1、NRAS、KRAS、MEK1(也称为MAP2K1)和MEK2(也称为MAP2K2)突变的患者中观察到了反应。与观察到的反应一致，我们在这些患者中发现的突变的特征证实，MAPK途径突变正在激活。总而言之，这些数据表明，组织细胞肿瘤的特征是显著依赖MAPK信号--因此它们对MEK抑制有反应。这些结果将分子靶向治疗的益处扩展到整个组织细胞增多症患者的光谱。
Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway(1,2). For the 50% of patients with histiocytosis who have BRAF(V600) mutations(3-5), RAF inhibition is highly efficacious and has markedly altered the natural history of the disease(6,7). However, no standard therapy exists for the remaining 50% of patients who lack BRAF(V600) mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAF(V600) mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.