Badodi, Sara;
Pomella, Nicola;
Lim, Yau Mun;
Brandner, Sebastian;
Morrison, Gillian;
Pollard, Steven M;
Zhang, Xinyu;
... Marino, Silvia; + view all
(2022)
Combination of BMI1 and MAPK/ERK inhibitors is effective in medulloblastoma.
Neuro-Oncology
, Article noac052. 10.1093/neuonc/noac052.
(In press).
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Abstract
BACKGROUND: Epigenetic changes play a key role in the pathogenesis of medulloblastoma (MB), the most common malignant paediatric brain tumour. METHODS: We explore the therapeutic potential of BMI1 and MAPK/ERK inhibition in BMI1 High;CHD7 Low MB cells and in a pre-clinical xenograft model. RESULTS: We identify a synergistic vulnerability of BMI1 High;CHD7 Low 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 anti-tumour effect of the inhibitors in vitro and in a pre-clinical mouse model. Increased ERK1 and ERK2 phosphorylation activity is found in BMI1 High;CHD7 Low 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 BMI1 High;CHD7 Low 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.
| Type: | Article |
|---|---|
| Title: | Combination of BMI1 and MAPK/ERK inhibitors is effective in medulloblastoma |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/neuonc/noac052 |
| Publisher version: | https://doi.org/10.1093/neuonc/noac052 |
| Language: | English |
| Additional information: | © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | BMI1, CHD7, MAPK/ERK, epigenetic, medulloblastoma |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10144763 |
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