Combination of BMI1 and MAPK/ERK inhibitors is effective in medulloblastoma.

Autor:	Badodi S; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Pomella N; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Lim YM; UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK., Brandner S; UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK., Morrison G; Centre for Regenerative Medicine & Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK., Pollard SM; Centre for Regenerative Medicine & Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK., Zhang X; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Zabet NR; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Marino S; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2022 Aug 01; Vol. 24 (8), pp. 1273-1285.
DOI:	10.1093/neuonc/noac052
Abstrakt:	Background: Epigenetic changes play a key role in the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor. Methods: We explore the therapeutic potential of BMI1 and MAPK/ERK inhibition in BMI1High;CHD7Low MB cells and in a preclinical xenograft model. Results: 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. Conclusions: 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. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
Databáze:	MEDLINE
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