索尼克刺猬 (Sonic Hedgehog, SHH) 髓母细胞瘤 (medulloblastomas, MBs) 表现出中等预后和广泛的肿瘤间异质性。虽然SHH通路拮抗剂对于青春期后的患者有效，但年轻的患者则表现出明显的副作用，并且携带下游SHH通路基因突变的肿瘤会对药物产生抗药性。因此，需要进行新型靶向治疗的研究。本研究在体外和体内研究了强效MEK抑制剂(trametinib)对2种人类和3种小鼠SHH MB模型的肿瘤特性的预临床检测，并在3种原位MB异种移植模型中进行了研究。Trametinib显著减小了肿瘤球大小，干细胞/前体细胞增殖、存活和迁移。对受trametinib处理的人类和小鼠细胞进行RNA测序分析，证实了这些发现，细胞周期、干细胞通路和SHH通路相关基因的表达减少，与此同时，与细胞死亡和纤毛病相关的基因表达增加。重要的是，trametinib也减少了肿瘤生长并延长了体内的存活时间。与行车线关联的E2F靶基因集在trametinib处理的肿瘤球和原位移植物中都普遍下调。然而，IL6/JAK STAT3和TNFα/NFκB信号传导基因集在长期MEK抑制后trametinib处理后特异性上调，表明补偿性分子变化。我们的研究揭示了trametinib在有效减弱SHH MB肿瘤进展方面的新角色，并值得进一步探究该强效MEK1/2抑制剂单独或与其他靶向治疗方法联合治疗SHH MB，其MAPK通路活性升高。©2023.Cell Death Differentiation Association (ADMC).

Sonic Hedgehog (SHH) medulloblastomas (MBs) exhibit an intermediate prognosis and extensive intertumoral heterogeneity. While SHH pathway antagonists are effective in post-pubertal patients, younger patients exhibit significant side effects, and tumors that harbor mutations in downstream SHH pathway genes will be drug resistant. Thus, novel targeted therapies are needed. Here, we performed preclinical testing of the potent MEK inhibitor (MEKi) trametinib on tumor properties across 2 human and 3 mouse SHH MB models in vitro and in 3 orthotopic MB xenograft models in vivo. Trametinib significantly reduces tumorsphere size, stem/progenitor cell proliferation, viability, and migration. RNA-sequencing on human and mouse trametinib treated cells corroborated these findings with decreased expression of cell cycle, stem cell pathways and SHH-pathway related genes concomitant with increases in genes associated with cell death and ciliopathies. Importantly, trametinib also decreases tumor growth and increases survival in vivo. Cell cycle related E2F target gene sets are significantly enriched for genes that are commonly downregulated in both trametinib treated tumorspheres and primary xenografts. However, IL6/JAK STAT3 and TNFα/NFκB signaling gene sets are specifically upregulated following trametinib treatment in vivo indicative of compensatory molecular changes following long-term MEK inhibition. Our study reveals a novel role for trametinib in effectively attenuating SHH MB tumor progression and warrants further investigation of this potent MEK1/2 inhibitor either alone or in combination with other targeted therapies for the treatment of SHH MB exhibiting elevated MAPK pathway activity.© 2023. Cell Death Differentiation Association (ADMC).