Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma
Name
s41467-019-10307-9.pdf
Description
Published version
Size
1.82 MB
Format
Adobe PDF
Checksum (MD5)
0680eaa5f836906acb3ddb46e49f3803
Author(s)
Bandopadhayay, Pratiti
Piccioni, Federica
O’Rourke, Ryan
Ho, Patricia
Gonzalez, Elizabeth M.
Buchan, Graham
Qian, Kenin
Gionet, Gabrielle
Girard, Emily
Coxon, Margo
Date Issued
June 2019
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Bandopadhayay, P. et al. "Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma." Nature Communications 10, 1 (June 2019): 2400 © 2019 The Author(s)
Version
Final published version
Abstract
BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi’s response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/s41467-019-10307-9
