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BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.ORCID iD: 0000-0003-2835-1518
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2019 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 10, article id 881Article in journal (Refereed) Published
Abstract [en]

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN-elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 10, article id 881
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Cancer and Oncology Cell Biology
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URN: urn:nbn:se:uu:diva-398423DOI: 10.1038/s41419-019-2120-1ISI: 000497973200005PubMedID: 31754113OAI: oai:DiVA.org:uu-398423DiVA, id: diva2:1375971
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish Society of MedicineRagnar Söderbergs stiftelseSwedish Childhood Cancer FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceAvailable from: 2019-12-06 Created: 2019-12-06 Last updated: 2019-12-06Bibliographically approved

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Bolin, SaraRosén, GabrielaWestermark, BengtNelander, SvenForsberg Nilsson, KarinUhrbom, LeneWeishaupt, HolgerJohansson, Fredrik K.
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