Selumetinib normalizes Ras/MAPK signaling in clinically relevant neurofibromatosis type 1 minipig tissues in vivo.
Selumetinib normalizes Ras/MAPK signaling in clinically relevant neurofibromatosis type 1 minipig tissues in vivo.
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DOI：
10.1093/noajnl/vdab020
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发表时间：
2021-01
期刊：
影响因子：
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通讯作者：
Watson AL
中科院分区：
文献类型：
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作者：
Osum SH;Coutts AW;Duerre DJ;Tschida BR;Kirstein MN;Fisher J;Bell WR;Delpuech O;Smith PD;Widemann BC;Moertel CL;Largaespada DA;Watson AL
MEK 1/2抑制剂selumetinib最近被批准用于1型神经纤维瘤病（NF 1）相关的丛状神经纤维瘤，但结果可能会改善，其在其他相关组织中的药效学评价有限。本研究的目的是使用NF 1小型猪模型评估司美替尼的组织药代动力学（PK）和药效学（PD）。WT（n = 8）和NF 1（n = 8）小型猪接受7.3 mg/kg司美替尼的单次口服剂量。收集外周血单核细胞（PBMC）、大脑皮层、视神经、坐骨神经和皮肤用于细胞外调节激酶磷酸化（p-ERK）抑制和转录物生物标志物（DUSP 6 & FOS）的PK分析和PD分析。关键司美替尼PK参数与人类患者中观察到的参数一致。与WT动物相比，NF 1动物CNS组织中的司美替尼浓度更高。所有小型猪的外周血单个核细胞（平均减少60%）、皮肤（95%）和坐骨神经（64%）均实现了对ERK磷酸化的抑制，而仅在NF 1动物中检测到对大脑皮质中ERK磷酸化的抑制（71%）。与WT相比，NF 1小型猪视神经中的基础p-ERK水平显著更高，并且使用司美替尼时降低至WT水平（60%）。在所有组织中观察到转录物生物标志物的调节。司美替尼降低了临床上与NF 1相关的组织中的MAPK信号传导，有效地使视神经中的p-ERK水平正常化至WT水平，但导致皮肤中的p-ERK水平异常低。这些结果表明，司美替尼通过使Ras/MAPK信号正常化而在NF 1相关CNS肿瘤中发挥活性，并可能解释常见的MEK受体相关皮肤毒性。
The MEK1/2 inhibitor selumetinib was recently approved for neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas, but outcomes could be improved and its pharmacodynamic evaluation in other relevant tissues is limited. The aim of this study was to assess selumetinib tissue pharmacokinetics (PK) and pharmacodynamics (PD) using a minipig model of NF1. WT (n = 8) and NF1 (n = 8) minipigs received a single oral dose of 7.3 mg/kg selumetinib. Peripheral blood mononuclear cells (PBMCs), cerebral cortex, optic nerve, sciatic nerve, and skin were collected for PK analysis and PD analysis of extracellular regulated kinase phosphorylation (p-ERK) inhibition and transcript biomarkers (DUSP6 & FOS). Key selumetinib PK parameters aligned with those observed in human patients. Selumetinib concentrations were higher in CNS tissues from NF1 compared to WT animals. Inhibition of ERK phosphorylation was achieved in PBMCs (mean 60% reduction), skin (95%), and sciatic nerve (64%) from all minipigs, whereas inhibition of ERK phosphorylation in cerebral cortex was detected only in NF1 animals (71%). Basal p-ERK levels were significantly higher in NF1 minipig optic nerve compared to WT and were reduced to WT levels (60%) with selumetinib. Modulation of transcript biomarkers was observed in all tissues. Selumetinib reduces MAPK signaling in tissues clinically relevant to NF1, effectively normalizing p-ERK to WT levels in optic nerve but resulting in abnormally low levels of p-ERK in the skin. These results suggest that selumetinib exerts activity in NF1-associated CNS tumors by normalizing Ras/MAPK signaling and may explain common MEK inhibitor-associated dermatologic toxicities.
影响因子：
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作者：
de Vries M;van Tellingen O;van der Mey AGL;Bunt AMG;Bruijn IB;Hogendoorn PCW
通讯作者：
Hogendoorn PCW