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Nat Commun. 2019 Jun 3;10(1):2400. doi: 10.1038/s41467-019-10307-9.

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

Author information

1
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
2
Broad Institute of MIT and Harvard, Cambridge, USA.
3
Department of Pediatrics, Harvard Medical School, Boston, USA.
4
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA.
5
Division of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA.
6
Department of Neurosurgery, Brigham and Women's Hospital, Boston, USA.
7
Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.
8
Department of Medicine and Surgery, Hematology and BMT, University of Parma, Parma, Italy.
9
Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Boston, USA.
10
Department of Pathology, Brigham and Women's Hospital, Boston, USA.
11
Department of Biomedical Informatics, Harvard Medical School, Boston, USA.
12
Laboratory of Systems Pharmacology, Harvard Medical School, Boston, USA.
13
Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, USA.
14
Discovery Science, Janssen Research and Development (Johnson & Johnson), Spring House, PA, USA.
15
Koch Institute for Integrative Cancer Research, MIT, Cambridge, USA.
16
Department of Medicine, Harvard Medical School, Boston, USA.
17
Novartis Institutes for Biomedical Research, Basel, Switzerland.
18
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
19
CCU Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
20
Department of Pediatric Oncology, Hematology, and Immunology, Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany.
21
Division of Pediatric Neuro-Oncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
22
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
23
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, USA.
24
Department of Pathology, Boston Children's Hospital, Boston, USA.
25
Broad Institute of MIT and Harvard, Cambridge, USA. cory.johannessen@gmail.com.
26
Broad Institute of MIT and Harvard, Cambridge, USA. Rameen_Beroukhim@dfci.harvard.edu.
27
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA. Rameen_Beroukhim@dfci.harvard.edu.
28
Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA. Rameen_Beroukhim@dfci.harvard.edu.
29
Department of Medicine, Harvard Medical School, Boston, USA. Rameen_Beroukhim@dfci.harvard.edu.

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.

PMID:
31160565
PMCID:
PMC6546744
DOI:
10.1038/s41467-019-10307-9
[Indexed for MEDLINE]
Free PMC Article

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