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.

BET-bromodomain inhibitors could be used to treat medulloblastoma tumors with Myc amplifications. Here, the authors show that both the response and resistance to BET inhibitors in mice is mediated by bHLH/homeobox transcription factors.

Details

Title
Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma
Author
Bandopadhayay, Pratiti 1 ; Piccioni, Federica 2   VIAFID ORCID Logo  ; O’Rourke, Ryan 3 ; Ho, Patricia 3 ; Gonzalez, Elizabeth M. 3 ; Buchan, Graham 3 ; Qian, Kenin 3 ; Gionet, Gabrielle 3 ; Girard, Emily 4 ; Coxon, Margo 4 ; Rees, Matthew G. 2   VIAFID ORCID Logo  ; Brenan, Lisa 2 ; Dubois, Frank 5 ; Shapira, Ofer 5 ; Greenwald, Noah F. 6   VIAFID ORCID Logo  ; Pages, Melanie 7 ; Balboni Iniguez, Amanda 3 ; Paolella, Brenton R. 5 ; Meng, Alice 8 ; Sinai, Claire 9 ; Roti, Giovanni 10 ; Dharia, Neekesh V. 11   VIAFID ORCID Logo  ; Creech, Amanda 2 ; Tanenbaum, Benjamin 2 ; Khadka, Prasidda 12 ; Tracy, Adam 2 ; Tiv, Hong L. 13   VIAFID ORCID Logo  ; Hong, Andrew L. 12   VIAFID ORCID Logo  ; Coy, Shannon 14 ; Rashid, Rumana 15 ; Lin, Jia-Ren 16   VIAFID ORCID Logo  ; Cowley, Glenn S. 17   VIAFID ORCID Logo  ; Lam, Fred C. 18 ; Goodale, Amy 2 ; Lee, Yenarae 2 ; Schoolcraft, Kathleen 8 ; Vazquez, Francisca 2   VIAFID ORCID Logo  ; Hahn, William C. 19   VIAFID ORCID Logo  ; Tsherniak, Aviad 2   VIAFID ORCID Logo  ; Bradner, James E. 20   VIAFID ORCID Logo  ; Yaffe, Michael B. 21 ; Milde, Till 22 ; Pfister, Stefan M. 23 ; Qi, Jun 24 ; Schenone, Monica 2   VIAFID ORCID Logo  ; Carr, Steven A. 2 ; Ligon, Keith L. 25 ; Kieran, Mark W. 26 ; Santagata, Sandro 27   VIAFID ORCID Logo  ; Olson, James M. 4 ; Gokhale, Prafulla C. 28 ; Jaffe, Jacob D. 2   VIAFID ORCID Logo  ; Root, David E. 2   VIAFID ORCID Logo  ; Stegmaier, Kimberly 12 ; Johannessen, Cory M. 2 ; Beroukhim, Rameen 29   VIAFID ORCID Logo 

1  Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, USA; Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Harvard Medical School, Department of Pediatrics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
2  Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) 
3  Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, USA (GRID:grid.66859.34); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) 
4  Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, USA (GRID:grid.270240.3) (ISNI:0000 0001 2180 1622) 
5  Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Dana-Farber Cancer Institute, Division of Cancer Biology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910) 
6  Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Dana-Farber Cancer Institute, Division of Cancer Biology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910); Brigham and Women’s Hospital, Department of Neurosurgery, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
7  Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, USA (GRID:grid.62560.37); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) 
8  Dana-Farber Cancer Institute, Division of Medical Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910) 
9  Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, USA (GRID:grid.65499.37); Dana-Farber Cancer Institute, Division of Medical Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910) 
10  Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, USA (GRID:grid.65499.37); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); University of Parma, Department of Medicine and Surgery, Hematology and BMT, Parma, Italy (GRID:grid.10383.39) (ISNI:0000 0004 1758 0937) 
11  Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, USA (GRID:grid.10383.39); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Harvard Medical School, Department of Pediatrics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
12  Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, USA (GRID:grid.66859.34); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Harvard Medical School, Department of Pediatrics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
13  Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Boston, USA (GRID:grid.66859.34) 
14  Brigham and Women’s Hospital, Department of Pathology, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
15  Brigham and Women’s Hospital, Department of Pathology, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Harvard Medical School, Department of Biomedical Informatics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
16  Harvard Medical School, Laboratory of Systems Pharmacology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Harvard Medical School, Ludwig Center for Cancer Research at Harvard, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
17  Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Janssen Research and Development (Johnson & Johnson), Discovery Science, Spring House, USA (GRID:grid.497530.c) (ISNI:0000 0004 0389 4927) 
18  Koch Institute for Integrative Cancer Research, MIT, Cambridge, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786) 
19  Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Dana-Farber Cancer Institute, Division of Medical Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910); Harvard Medical School, Department of Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
20  Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Dana-Farber Cancer Institute, Division of Medical Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910); Harvard Medical School, Department of Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Novartis Institutes for Biomedical Research, Basel, Switzerland (GRID:grid.419481.1) (ISNI:0000 0001 1515 9979) 
21  Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Koch Institute for Integrative Cancer Research, MIT, Cambridge, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786) 
22  Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany (GRID:grid.116068.8); CCU Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); Heidelberg University Hospital, Department of Pediatric Oncology, Hematology, and Immunology, Center for Child and Adolescent Medicine, Heidelberg, Germany (GRID:grid.5253.1) (ISNI:0000 0001 0328 4908) 
23  Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany (GRID:grid.5253.1); German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Division of Pediatric Neuro-Oncology, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); Heidelberg University Hospital, Department of Pediatric Hematology and Oncology, Heidelberg, Germany (GRID:grid.5253.1) (ISNI:0000 0001 0328 4908) 
24  Dana-Farber Cancer Institute, Division of Cancer Biology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910) 
25  Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Brigham and Women’s Hospital, Department of Pathology, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Harvard Medical School, Department of Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Dana-Farber Cancer Institute, Department of Oncologic Pathology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910); Boston Children’s Hospital, Department of Pathology, Boston, USA (GRID:grid.2515.3) (ISNI:0000 0004 0378 8438) 
26  Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, USA (GRID:grid.2515.3); Harvard Medical School, Department of Pediatrics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
27  Dana-Farber Cancer Institute, Division of Medical Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910); Brigham and Women’s Hospital, Department of Pathology, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
28  Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Boston, USA (GRID:grid.270240.3) 
29  Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, USA (GRID:grid.270240.3) (ISNI:0000 0001 2180 1622); Dana-Farber Cancer Institute, Division of Medical Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910); Harvard Medical School, Department of Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
Pages
2400
Publication year
2019
Publication date
2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-10307-9
ProQuest document ID
2822568352
Copyright
© The Author(s) 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.