Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma.

Integrative genomic analysis to identify mediators of BETi response

Bandopadhayay et al. (2019) Nat Commun. CC BY 4.0

Bandopadhayay P, Piccioni F, O'Rourke R, Ho P, Gonzalez EM, Buchan G, Qian K, Gionet G, Girard E, Coxon M, Rees MG, Brenan L, Dubois F, Shapira O, Greenwald NF, Pages M, Balboni Iniguez A, Paolella BR, Meng A, Sinai C, Roti G, Dharia NV, Creech A, Tanenbaum B, Khadka P, Tracy A, Tiv HL, Hong AL, Coy S, Rashid R, Lin JR, Cowley GS, Lam FC, Goodale A, Lee Y, Schoolcraft K, Vazquez F, Hahn WC, Tsherniak A, Bradner JE, Yaffe MB, Milde T, Pfister SM, Qi J, Schenone M, Carr SA, Ligon KL, Kieran MW, Santagata S, Olson JM, Gokhale PC, Jaffe JD, Root DE, Stegmaier K, Johannessen CM, Beroukhim R.

Nature Communications

June 03, 2019

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.

Last updated: June 20, 2019