Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma
2019
BET-
bromodomaininhibition (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/
homeoboxtranscription factors and cell-cycle regulators as key genes mediating BETi’s response and resistance. Cells that acquire
drug toleranceexhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/
homeoboxtranscription 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.
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