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

Pratiti Bandopadhayay, Federica Piccioni, Ryan O’Rourke, Patricia Ho, Elizabeth M. Gonzalez, Graham Buchan, Kenin Qian, Gabrielle Gionet, Emily Girard, Margo Coxon, Matthew G. Rees, Lisa Brenan, Frank Dubois, Ofer Shapira, Noah F. Greenwald, Melanie Pages, Amanda Balboni Iniguez, Brenton R. Paolella, Alice Meng, Claire Sinai, Giovanni Roti, Neekesh V. Dharia, Amanda Creech, Benjamin Tanenbaum, Prasidda Khadka, Adam Tracy, Hong L. Tiv, Andrew L. Hong, Shannon Coy, Rumana Rashid, Jia-Ren Lin, Glenn S. Cowley, Fred C. Lam, Amy Goodale, Yenarae Lee, Kathleen Schoolcraft, Francisca Vazquez, William C. Hahn, Aviad Tsherniak, James E. Bradner, Michael B. Yaffe, Till Milde, Stefan M. Pfister, Jun Qi, Monica Schenone, Steven A. Carr, Keith L. Ligon, Mark W. Kieran, Sandro Santagata, James M. Olson, Prafulla C. Gokhale, Jacob D. Jaffe, David E. Root, Kimberly Stegmaier, Cory M. Johannessen () and Rameen Beroukhim ()
Additional contact information
Pratiti Bandopadhayay: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Federica Piccioni: Broad Institute of MIT and Harvard
Ryan O’Rourke: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Patricia Ho: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Elizabeth M. Gonzalez: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Graham Buchan: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Kenin Qian: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Gabrielle Gionet: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Emily Girard: Fred Hutchinson Cancer Research Center
Margo Coxon: Fred Hutchinson Cancer Research Center
Matthew G. Rees: Broad Institute of MIT and Harvard
Lisa Brenan: Broad Institute of MIT and Harvard
Frank Dubois: Broad Institute of MIT and Harvard
Ofer Shapira: Broad Institute of MIT and Harvard
Noah F. Greenwald: Broad Institute of MIT and Harvard
Melanie Pages: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Amanda Balboni Iniguez: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Brenton R. Paolella: Broad Institute of MIT and Harvard
Alice Meng: Dana-Farber Cancer Institute
Claire Sinai: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Giovanni Roti: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Neekesh V. Dharia: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Amanda Creech: Broad Institute of MIT and Harvard
Benjamin Tanenbaum: Broad Institute of MIT and Harvard
Prasidda Khadka: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Adam Tracy: Broad Institute of MIT and Harvard
Hong L. Tiv: Experimental Therapeutics Core and Belfer Center for Applied Cancer Science
Andrew L. Hong: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Shannon Coy: Brigham and Women’s Hospital
Rumana Rashid: Brigham and Women’s Hospital
Jia-Ren Lin: Harvard Medical School
Glenn S. Cowley: Broad Institute of MIT and Harvard
Fred C. Lam: Koch Institute for Integrative Cancer Research, MIT
Amy Goodale: Broad Institute of MIT and Harvard
Yenarae Lee: Broad Institute of MIT and Harvard
Kathleen Schoolcraft: Dana-Farber Cancer Institute
Francisca Vazquez: Broad Institute of MIT and Harvard
William C. Hahn: Broad Institute of MIT and Harvard
Aviad Tsherniak: Broad Institute of MIT and Harvard
James E. Bradner: Broad Institute of MIT and Harvard
Michael B. Yaffe: Broad Institute of MIT and Harvard
Till Milde: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Stefan M. Pfister: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Jun Qi: Dana-Farber Cancer Institute
Monica Schenone: Broad Institute of MIT and Harvard
Steven A. Carr: Broad Institute of MIT and Harvard
Keith L. Ligon: Broad Institute of MIT and Harvard
Mark W. Kieran: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Sandro Santagata: Dana-Farber Cancer Institute
James M. Olson: Fred Hutchinson Cancer Research Center
Prafulla C. Gokhale: Experimental Therapeutics Core and Belfer Center for Applied Cancer Science
Jacob D. Jaffe: Broad Institute of MIT and Harvard
David E. Root: Broad Institute of MIT and Harvard
Kimberly Stegmaier: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Cory M. Johannessen: Broad Institute of MIT and Harvard
Rameen Beroukhim: Broad Institute of MIT and Harvard

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10307-9

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