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.
Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma / Bandopadhayay, P.; Piccioni, F.; O'Rourke, R.; Ho, P.; Gonzalez, E. M.; Buchan, G.; Qian, K.; Gionet, G.; Girard, E.; Coxon, M.; Rees, M. G.; Brenan, L.; Dubois, F.; Shapira, O.; Greenwald, N. F.; Pages, M.; Balboni Iniguez, A.; Paolella, B. R.; Meng, A.; Sinai, C.; Roti, G.; Dharia, N. V.; Creech, A.; Tanenbaum, B.; Khadka, P.; Tracy, A.; Tiv, H. L.; Hong, A. L.; Coy, S.; Rashid, R.; Lin, J. -R.; Cowley, G. S.; Lam, F. C.; Goodale, A.; Lee, Y.; Schoolcraft, K.; Vazquez, F.; Hahn, W. C.; Tsherniak, A.; Bradner, J. E.; Yaffe, M. B.; Milde, T.; Pfister, S. M.; Qi, J.; Schenone, M.; Carr, S. A.; Ligon, K. L.; Kieran, M. W.; Santagata, S.; Olson, J. M.; Gokhale, P. C.; Jaffe, J. D.; Root, D. E.; Stegmaier, K.; Johannessen, C. M.; Beroukhim, R.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019), p. 2400. [10.1038/s41467-019-10307-9]
Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma
Roti G.;
2019-01-01
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
