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| Status |
Public on Dec 05, 2019 |
| Title |
BET and Aurora Kinase A Inhibitors Synergize against MYCN-positive Human Glioblastoma Cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 sensitive cells. Bioinformatic analyses showed that JQ1-sensitive cells could also respond to Aurora Kinase A inhibition which indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibition could potentiate the efficacy of TMZ or could be combined with Aurora Kinase inhibitors in MYCN-elevated GBM.
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| Overall design |
A total of 24 samples were profiled for RNA expression; four tumor derived cell lines were pertubed in triplicates with either JQ1 drug or DMSO.
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| Contributor(s) |
Čančer M, Drews LF, Bengtsson J, Bolin S, Rosén G, Westermark B, Nelander S, Forsberg-Nilsson K, Uhrbom L, Weishaupt H, Swartling FJ |
| Citation(s) |
31754113 |
| Submission date |
Oct 16, 2019 |
| Last update date |
Dec 05, 2019 |
| Contact name |
Fredrik Johansson Swartling |
| Organization name |
Uppsala University
|
| Department |
Immunology, Genetics and Pathology
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| Street address |
Dag Hammarskjölds väg 20
|
| City |
Uppsala |
| ZIP/Postal code |
752 37 |
| Country |
Sweden |
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| Platforms (1) |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA577866 |
| SRA |
SRP225897 |
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