PDF(Pubmed)
Abstract：
The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low-grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.
摘要：
遗传综合征1型神经纤维瘤病（NF1）的各种临床表现是由RAS途径的过度激活驱动的。丝裂原活化蛋白激酶激酶抑制剂（MEKi）阻断RAS的下游靶标。最近监管批准的MEKi司米替尼用于NF1儿童无法手术的症状性丛状神经纤维瘤，使其成为美国第一个批准用于该适应症的药物治疗。欧洲联盟,和其他地方。最近发表和正在进行的一些临床试验表明，MEKi可能对各种其他NF1表现有潜在的好处，并且对这些药物的适当临床应用有广泛的兴趣。在这次审查中,我们提供了有关使用现有MEKi进行多种NF1相关表现的当前证据，包括肿瘤（神经纤维瘤，恶性周围神经鞘瘤，低度胶质瘤,和幼年粒单核细胞白血病)和非肿瘤(骨，疼痛,和神经认知)表现。我们讨论了MEKi在以RAS途径过度激活（RASopathies）为特征的相关遗传条件中的潜在用途。此外,我们回顾了使用MEKi的实际治疗考虑因素,并就其临床使用提供了专家小组的共识建议.
