Drug-based perturbation screen uncovers synergistic drug combinations in Burkitt lymphoma
| Autor: | Tatjana Walther, Lena Wagner, Małgorzata Oleś, Benedikt Brors, Wolfgang Huber, Thorsten Zenz, Jennifer Hüllein, Leopold Sellner, Roman Vladimirovich Kurilov, Marina Lukas, Katarzyna Tomska, Kwang Seok Lee |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
lcsh:Medicine Antineoplastic Agents Article BET inhibitor 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cyclin-dependent kinase Cell Line Tumor Agammaglobulinaemia Tyrosine Kinase medicine Humans Bruton's tyrosine kinase Doxorubicin lcsh:Science Oxazoles Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Sulfonamides Multidisciplinary biology Kinase Venetoclax lcsh:R Drug Synergism Bridged Bicyclo Compounds Heterocyclic Burkitt Lymphoma Drug Combinations Thiazoles 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 chemistry 030220 oncology & carcinogenesis Cancer research biology.protein Acetanilides lcsh:Q Heterocyclic Compounds 3-Ring medicine.drug |
| Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-12 (2018) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma associated with MYC translocation. Here, we describe drug response profiling of 42 blood cancer cell lines including 17 BL to 32 drugs targeting key cancer pathways and provide a systematic study of drug combinations in BL cell lines. Based on drug response, we identified cell line specific sensitivities, i.e. to venetoclax driven by BCL2 overexpression and partitioned subsets of BL driven by response to kinase inhibitors. In the combination screen, including BET, BTK and PI3K inhibitors, we identified synergistic combinations of PI3K and BTK inhibition with drugs targeting Akt, mTOR, BET and doxorubicin. A detailed comparison of PI3K and BTKi combinations identified subtle differences, in line with convergent pathway activity. Most synergistic combinations were identified for the BET inhibitor OTX015, which showed synergistic effects for 41% of combinations including inhibitors of PI3K/AKT/mTOR signalling. The strongest synergy was observed for the combination of the CDK 2/7/9 inhibitor SNS032 and OTX015. Our data provide a landscape of drug combination effects in BL and suggest that targeting CDK and BET could provide a novel vulnerability of BL. |
| Databáze: | OpenAIRE |
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