Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition.
Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition.
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DOI：
10.1038/s41390-022-01986-0
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发表时间：
2023-12
影响因子：
3.6
通讯作者：
Dagan, Adi
中科院分区：
文献类型：
--
作者：
Chowers, Guy;Abebe-Campino, Gadi;Golan, Hana;Vivante, Asaf;Greenberger, Shoshana;Soudack, Michalle;Barkai, Galia;Fox-Fisher, Ilana;Li, Dong;March, Michael;Battig, Mark R.;Hakonarson, Hakon;Adams, Denise;Dori, Yoav;Dagan, Adi
卡波西样淋巴管瘤病(KLA)是一种复杂的淋巴管畸形，常累及纵隔、肺、皮肤和骨骼，但缺乏有效的治疗方法。近年来，Ras-MAPK通路突变被证明是几种复杂淋巴异常的基础发病机制。具体地说，在大多数KLA患者中发现了一个激活的NRAS突变(p.Q61R)。最近的报道显示，在复杂淋巴异常患者中，MEK抑制剂曲美替尼的治疗结果令人振奋，这些患者存在ARAF和SOS1功能突变的增加，以及RAS-MAPK途径的负调控因子CBL基因功能突变的丢失。我们报告了一例9岁的重症KLA患儿，其血浆来源的游离细胞DNA检测到了典型的NRAS(p.Q61R)突变，对曲美替尼治疗有反应。用三维球体发芽试验同时进行了曲美替尼对受突变的NRAS影响的淋巴管内皮细胞活性的体外研究。结果曲美替尼治疗导致终生血小板减少症的缓解，肺功能测试和幸福感的改善，以及长期全身类固醇治疗的戒断。同时对表达NRAS的突变细胞的研究显示，表达NRAS的突变细胞的淋巴管生成能力增强，同时RAS-MAPK和PI3K-AKT-mTOR通路被曲美替尼逆转。结论曲美替尼治疗可以显著改变RAS途径相关淋巴管异常患者的预后。这是首次描述了曲美替尼治疗具有最具特征的NRAS p.Q61R突变的KLA患者的成功。治疗可以显著改变RAS途径相关淋巴管异常患者的预后。我们设计了一种KLA体外模型，为继续研究疾病的发病机制提供了一种可复制的方法。突变的NRAS P.Q61R细胞证实了淋巴管生成能力的增加。
BackgroundKaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy.MethodsThe NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay.ResultsTrametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib.ConclusionsTrametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies.ImpactThis is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation.Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies.We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis.Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.
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影响因子：
3.2
作者：
Crane J;Manfredo J;Boscolo E;Coyan M;Takemoto C;Itkin M;Adams DM;Le Cras TD
通讯作者：
Le Cras TD
影响因子：
5.7
作者：
Bhagwat, Shripad V.;Gokhale, Prafulla C.;Pachter, Jonathan A.
通讯作者：
Pachter, Jonathan A.
影响因子：
51.1
作者：
Dummer, Reinhard;Schadendorf, Dirk;Flaherty, Keith
通讯作者：
Flaherty, Keith
DOI：
10.1016/j.jpeds.2013.10.013
发表时间：
2014-02
期刊：
The Journal of pediatrics
影响因子：
--
作者：
Croteau SE;Kozakewich HP;Perez-Atayde AR;Fishman SJ;Alomari AI;Chaudry G;Mulliken JB;Trenor CC 3rd
通讯作者：
Trenor CC 3rd
影响因子：
1.5
作者：
Seo, SK;Suh, JC;Sohn, KR
通讯作者：
Sohn, KR