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

Autor: Bandopadhayay P; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA.; Department of Pediatrics, Harvard Medical School, Boston, USA., Piccioni F; Broad Institute of MIT and Harvard, Cambridge, USA., O'Rourke R; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA., Ho P; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA., Gonzalez EM; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA., Buchan G; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA., Qian K; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA., Gionet G; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA., Girard E; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA., Coxon M; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA., Rees MG; Broad Institute of MIT and Harvard, Cambridge, USA., Brenan L; Broad Institute of MIT and Harvard, Cambridge, USA., Dubois F; Broad Institute of MIT and Harvard, Cambridge, USA.; Division of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA., Shapira O; Broad Institute of MIT and Harvard, Cambridge, USA.; Division of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA., Greenwald NF; Broad Institute of MIT and Harvard, Cambridge, USA.; Division of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA.; Department of Neurosurgery, Brigham and Women's Hospital, Boston, USA., Pages M; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA., Balboni Iniguez A; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA., Paolella BR; Broad Institute of MIT and Harvard, Cambridge, USA.; Division of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA., Meng A; Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA., Sinai C; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA., Roti G; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA.; Department of Medicine and Surgery, Hematology and BMT, University of Parma, Parma, Italy., Dharia NV; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA.; Department of Pediatrics, Harvard Medical School, Boston, USA., Creech A; Broad Institute of MIT and Harvard, Cambridge, USA., Tanenbaum B; Broad Institute of MIT and Harvard, Cambridge, USA., Khadka P; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA.; Department of Pediatrics, Harvard Medical School, Boston, USA., Tracy A; Broad Institute of MIT and Harvard, Cambridge, USA., Tiv HL; Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Boston, USA., Hong AL; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA.; Department of Pediatrics, Harvard Medical School, Boston, USA., Coy S; Department of Pathology, Brigham and Women's Hospital, Boston, USA., Rashid R; Department of Pathology, Brigham and Women's Hospital, Boston, USA.; Department of Biomedical Informatics, Harvard Medical School, Boston, USA., Lin JR; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, USA.; Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, USA., Cowley GS; Broad Institute of MIT and Harvard, Cambridge, USA.; Discovery Science, Janssen Research and Development (Johnson & Johnson), Spring House, PA, USA., Lam FC; Koch Institute for Integrative Cancer Research, MIT, Cambridge, USA., Goodale A; Broad Institute of MIT and Harvard, Cambridge, USA., Lee Y; Broad Institute of MIT and Harvard, Cambridge, USA., Schoolcraft K; Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA., Vazquez F; Broad Institute of MIT and Harvard, Cambridge, USA., Hahn WC; Broad Institute of MIT and Harvard, Cambridge, USA.; Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.; Department of Medicine, Harvard Medical School, Boston, USA., Tsherniak A; Broad Institute of MIT and Harvard, Cambridge, USA., Bradner JE; Broad Institute of MIT and Harvard, Cambridge, USA.; Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.; Department of Medicine, Harvard Medical School, Boston, USA.; Novartis Institutes for Biomedical Research, Basel, Switzerland., Yaffe MB; Broad Institute of MIT and Harvard, Cambridge, USA.; Koch Institute for Integrative Cancer Research, MIT, Cambridge, USA., Milde T; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.; CCU Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Pediatric Oncology, Hematology, and Immunology, Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany., Pfister SM; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.; Division of Pediatric Neuro-Oncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany., Qi J; Division of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA., Schenone M; Broad Institute of MIT and Harvard, Cambridge, USA., Carr SA; Broad Institute of MIT and Harvard, Cambridge, USA., Ligon KL; Broad Institute of MIT and Harvard, Cambridge, USA.; Department of Pathology, Brigham and Women's Hospital, Boston, USA.; Department of Medicine, Harvard Medical School, Boston, USA.; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, USA.; Department of Pathology, Boston Children's Hospital, Boston, USA., Kieran MW; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Department of Pediatrics, Harvard Medical School, Boston, USA., Santagata S; Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.; Department of Pathology, Brigham and Women's Hospital, Boston, USA., Olson JM; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA., Gokhale PC; Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Boston, USA., Jaffe JD; Broad Institute of MIT and Harvard, Cambridge, USA., Root DE; Broad Institute of MIT and Harvard, Cambridge, USA., Stegmaier K; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.; Broad Institute of MIT and Harvard, Cambridge, USA.; Department of Pediatrics, Harvard Medical School, Boston, USA., Johannessen CM; Broad Institute of MIT and Harvard, Cambridge, USA. cory.johannessen@gmail.com., Beroukhim R; Broad Institute of MIT and Harvard, Cambridge, USA. Rameen_Beroukhim@dfci.harvard.edu.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA. Rameen_Beroukhim@dfci.harvard.edu.; Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA. Rameen_Beroukhim@dfci.harvard.edu.; Department of Medicine, Harvard Medical School, Boston, USA. Rameen_Beroukhim@dfci.harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 Jun 03; Vol. 10 (1), pp. 2400. Date of Electronic Publication: 2019 Jun 03.
DOI: 10.1038/s41467-019-10307-9
Abstrakt: 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.
Databáze: MEDLINE