Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Ottawa Bioinformatics Core Facility, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Commun Biol. 2022 Jul 14;5(1):697. doi: 10.1038/s42003-022-03654-9.
Medulloblastoma (MB) is the most common primary malignant pediatric brain cancer. We recently identified novel roles for the MEK/MAPK pathway in regulating human Sonic Hedgehog (SHH) MB tumorigenesis. The MEK inhibitor, selumetinib, decreased SHH MB growth while extending survival in mouse models. However, the treated mice ultimately succumbed to disease progression. Here, we perform RNA sequencing on selumetinib-treated orthotopic xenografts to identify molecular pathways that compensate for MEK inhibition specifically in vivo. Notably, the JAK/STAT3 pathway exhibits increased activation in selumetinib-treated tumors. The combination of selumetinib and the JAK/STAT3 pathway inhibitor, pacritinib, further reduces growth in two xenograft models and also enhances survival. Multiplex spatial profiling of proteins in drug-treated xenografts reveals shifted molecular dependencies and compensatory changes following combination drug treatment. Our study warrants further investigation into MEK and JAK/STAT3 inhibition as a novel combinatory therapeutic strategy for SHH MB.
髓母细胞瘤（MB）是最常见的原发性小儿脑恶性肿瘤。我们最近发现 MEK/MAPK 通路在调节人类 Sonic Hedgehog（SHH）MB 肿瘤发生方面具有新的作用。MEK 抑制剂 selumetinib 可减少 SHH MB 的生长，同时延长小鼠模型的存活时间。然而，接受治疗的小鼠最终还是因疾病进展而死亡。在这里，我们对 selumetinib 处理的原位异种移植进行 RNA 测序，以鉴定在体内特异性补偿 MEK 抑制的分子途径。值得注意的是，JAK/STAT3 通路在 selumetinib 处理的肿瘤中表现出激活增加。selumetinib 和 JAK/STAT3 通路抑制剂 pacritinib 的联合使用进一步减少了两种异种移植模型中的肿瘤生长，并提高了存活率。药物处理的异种移植中蛋白质的多重空间分析揭示了在联合药物治疗后分子依赖性的变化和代偿性改变。我们的研究证明 MEK 和 JAK/STAT3 抑制作为 SHH MB 的一种新的联合治疗策略是值得进一步研究的。
