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Efficacy of MEK inhibition in patients with histiocytic neoplasms

机译：MEK抑制在组织细胞性肿瘤患者中的功效

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摘要

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.
机译：组织细胞性肿瘤是一类异种的克隆性造血疾病，其特征在于丝裂原活化蛋白激酶（MAPK）途径中的多种突变（1,2）。对于50％有BRAF（V600）突变的组织细胞病患者（3-5），RAF抑制作用非常有效，并且显着改变了疾病的自然病程（6,7）。但是，对于缺少BRAF（V600）突变的其余50％的患者，不存在标准疗法。尽管ERK依赖性被认为是组织细胞性肿瘤的一个一致特征，但是这在临床上尚未得到证实，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，我们通过概念验证性临床试验Cobimetinib（一种MEK1和MEK2的口服抑制剂）在组织细胞病患者中显示了组织细胞酶的ERK依赖性。不论患者的肿瘤基因型如何，均入组患者。同时，在治疗的患者中鉴定出的MAPK改变以激活ERK的能力为特征。在我们治疗的18例患者中，总缓解率为89％（90％的置信区间为73-100）。回应是持久的，迄今为止没有获得抵抗。一年后，100％的反应仍在进行，94％的患者无进展。 Cobimetinib治疗有效，无论其基因型如何，在具有ARAF，BRAF，RAF1，NRAS，KRAS，MEK1（也称为MAP2K1）和MEK2（也称为MAP2K2）突变的患者中均观察到反应。与观察到的反应一致，我们在这些患者中鉴定出的突变特征证实了MAPK途径突变正在激活。总的来说，这些数据证明组织细胞性肿瘤的特征在于对MAPK信号传导的显着依赖性，因此它们对MEK抑制具有响应性。这些结果将分子靶向治疗的益处扩展到了组织细胞增多症患者的整个范围。

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  • 来源
    《Nature》 |2019年第7749期|521-524|共4页
  • 作者

    Diamond Eli L.; Durham Benjamin H.; Ulaner Gary A.; Drill Esther; Buthorn Justin; Ki Michelle; Bitner Lillian; Cho Hana; Young Robert J.; Francis Jasmine H.; Rampal Raajit; Lacouture Mario; Brody Lynn A.; Ozkaya Neval; Dogan Ahmet; Rosen Neal; Iasonos Alexia; Abdel-Wahab Omar; Hyman David M.;

  • 作者单位

    Mem Sloan Kettering Canc Ctr, Dept Neurol, 1275 York Ave, New York, NY 10021 USA|Weill Cornell Med Coll, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA|Mem Sloan Kettering Canc Ctr, Dept Med, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA;

    Weill Cornell Med Coll, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA;

    Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA;

    Mem Sloan Kettering Canc Ctr, Dept Neurol, 1275 York Ave, New York, NY 10021 USA;

    Mem Sloan Kettering Canc Ctr, Dept Med, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA;

    Mem Sloan Kettering Canc Ctr, Dept Med, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA;

    Mem Sloan Kettering Canc Ctr, Dept Med, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA;

    Weill Cornell Med Coll, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA;

    Mem Sloan Kettering Canc Ctr, Dept Med, Ophthalm Oncol Serv, 1275 York Ave, New York, NY 10021 USA;

    Weill Cornell Med Coll, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA;

    Weill Cornell Med Coll, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Med, Dermatol Serv, New York, NY 10021 USA;

    Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA;

    Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA|NCI, Lab Pathol, Bethesda, MD 20892 USA;

    Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA;

    Weill Cornell Med Coll, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA|Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, 1275 York Ave, New York, NY 10021 USA;

    Weill Cornell Med Coll, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA;

    Weill Cornell Med Coll, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Med, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA|Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA;

    Weill Cornell Med Coll, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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