Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.
Neuro Oncol. 2022 Aug 1;24(8):1273-1285. doi: 10.1093/neuonc/noac052.
Epigenetic changes play a key role in the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor.
We explore the therapeutic potential of BMI1 and MAPK/ERK inhibition in BMI1High;CHD7Low MB cells and in a preclinical xenograft model.
We identify a synergistic vulnerability of BMI1High;CHD7Low MB cells to a combination treatment with BMI1 and MAPK/ERK inhibitors. Mechanistically, CHD7-dependent binding of BMI1 to MAPK-regulated genes underpins the CHD7-BMI1-MAPK regulatory axis responsible of the antitumour effect of the inhibitors in vitro and in a preclinical mouse model. Increased ERK1 and ERK2 phosphorylation activity is found in BMI1High;CHD7Low G4 MB patients, raising the possibility that they could be amenable to a similar therapy.
The molecular dissection of the CHD7-BMI1-MAPK regulatory axis in BMI1High;CHD7Low MB identifies this signature as a proxy to predict MAPK functional activation, which can be effectively drugged in preclinical models, and paves the way for further exploration of combined BMI1 and MAPK targeting in G4 MB patients.
表观遗传变化在成神经管细胞瘤（MB）的发病机制中起着关键作用，MB 是最常见的儿童脑部恶性肿瘤。
我们探索了 BMI1 和 MAPK/ERK 抑制在 BMI1High;CHD7Low MB 细胞中的治疗潜力，并在临床前异种移植模型中进行了研究。
我们发现 BMI1High;CHD7Low MB 细胞对 BMI1 和 MAPK/ERK 抑制剂联合治疗具有协同的脆弱性。从机制上讲，BMI1 与 MAPK 调节基因的 CHD7 依赖性结合为 CHD7-BMI1-MAPK 调节轴奠定了基础，该调节轴负责抑制剂在体外和临床前小鼠模型中的抗肿瘤作用。在 BMI1High;CHD7Low G4 MB 患者中发现 ERK1 和 ERK2 磷酸化活性增加，这表明他们可能适合接受类似的治疗。
对 BMI1High;CHD7Low MB 中 CHD7-BMI1-MAPK 调节轴的分子剖析将该特征确定为预测 MAPK 功能激活的替代物，该替代物可在临床前模型中有效靶向，为进一步探索 G4 MB 患者中 BMI1 和 MAPK 联合靶向治疗铺平了道路。
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