Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation

Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1(High);CHD7(Low) signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1(High);CHD7(Low) xenograft model. BMI1 and CHD7 are chromatin remodelling genes with a role in medulloblastoma pathogenesis. Here, the authors demonstrate that the BMI1(High)/CHD7(Low) signature mediates metabolic adaptation in G4 MB and predicts response to inositol treatment either alone or in combination with chemotherapy.