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Nat Commun DOI:10.1038/s41467-019-10307-9

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

Publication TypeJournal Article
Year of Publication2019
AuthorsBandopadhayay, 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, Iniguez, ABalboni, 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, J-R, 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
JournalNat Commun
Volume10
Issue1
Pages2400
Date Published2019 06 03
ISSN2041-1723
KeywordsAnimals, Azepines, Basic Helix-Loop-Helix Transcription Factors, Cell Cycle, Cell Cycle Proteins, Cell Line, Tumor, Cell Lineage, Cerebellar Neoplasms, CRISPR-Cas Systems, Cyclin D2, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Drug Resistance, Neoplasm, Gene Expression Profiling, Humans, Medulloblastoma, Mice, Neural Stem Cells, Neurogenesis, Proteins, Proto-Oncogene Proteins c-myc, S Phase, Triazoles
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.

DOI10.1038/s41467-019-10307-9
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/31160565?dopt=Abstract

Alternate JournalNat Commun
PubMed ID31160565
PubMed Central IDPMC6546744