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Bandopadhayay, Pratiti; Piccioni, Federica; O'Rourke, Ryan; Ho, Patricia; Gonzalez, Elizabeth M; Buchan, Graham; Qian, Kenin; Gionet, Gabrielle; Girard, Emily; Coxon, Margo; Rees, Matthew G; Brenan, Lisa; Dubois, Frank; Shapira, Ofer; Greenwald, Noah F; Pages, Melanie; Balboni Iniguez, Amanda; Paolella, Brenton R; Meng, Alice; Sinai, Claire; Roti, Giovanni; Dharia, Neekesh V; Creech, Amanda; Tanenbaum, Benjamin; Khadka, Prasidda; Tracy, Adam; Tiv, Hong L; Hong, Andrew L; Coy, Shannon; Rashid, Rumana; Lin, Jia-Ren; Cowley, Glenn S; Lam, Fred C; Goodale, Amy; Lee, Yenarae; Schoolcraft, Kathleen; Vazquez, Francisca; Hahn, William C; Tsherniak, Aviad; Bradner, James E; Yaffe, Michael B; Milde, Till; Pfister, Stefan M; Qi, Jun; Schenone, Monica; Carr, Steven A; Ligon, Keith L; Kieran, Mark W; Santagata, Sandro; Olson, James M; Gokhale, Prafulla C; Jaffe, Jacob D; Root, David E; Stegmaier, Kimberly; Johannessen, Cory M; Beroukhim, Rameen
Nature communications, 06/2019, Letnik: 10, Številka: 1Journal Article
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.
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in: SICRIS
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