|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||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, 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|
|Date Published||2019 06 03|
|Keywords||Animals, 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|
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.
|Alternate Journal||Nat Commun|
|PubMed Central ID||PMC6546744|