Schmidl, Christian and Vladimer, Gregory I. and Rendeiro, Andre F. and Schnabl, Susanne and Krausgruber, Thomas and Taubert, Christina and Krall, Nikolaus and Pemovska, Tea and Araghi, Mohammad and Snijder, Berend and Hubmann, Rainer and Ringler, Anna and Runggatscher, Kathrin and Demirtas, Dita and de la Fuente, Oscar Lopez and Hilgarth, Martin and Skrabs, Cathrin and Porpaczy, Edit and Gruber, Michaela and Hoermann, Gregor and Kubicek, Stefan and Staber, Philipp B. and Shehata, Medhat and Superti-Furga, Giulio and Jaeger, Ulrich and Bock, Christoph (2019) Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL. NATURE CHEMICAL BIOLOGY, 15 (3). 232-+. ISSN 1552-4450, 1552-4469
Full text not available from this repository. (Request a copy)Abstract
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib is not curative, it has a profound effect on CLL cells and may create new pharmacologically exploitable vulnerabilities. To identify such vulnerabilities, we developed a systematic approach that combines epigenome profiling (charting the gene-regulatory basis of cell state) with single-cell chemosensitivity profiling (quantifying cell-type-specific drug response) and bioinformatic data integration. By applying our method to a cohort of matched patient samples collected before and during ibrutinib therapy, we identified characteristic ibrutinib-induced changes that provide a starting point for the rational design of ibrutinib combination therapies. Specifically, we observed and validated preferential sensitivity to proteasome, PLK1, and mTOR inhibitors during ibrutinib treatment. More generally, our study establishes a broadly applicable method for investigating treatment-specific vulnerabilities by integrating the complementary perspectives of epigenetic cell states and phenotypic drug responses in primary patient samples.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHRONIC LYMPHOCYTIC-LEUKEMIA; B-CELL RECEPTOR; TYROSINE KINASE INHIBITION; THERAPEUTIC TARGET; OPEN-LABEL; IBRUTINIB; BTK; RESISTANCE; ANNOTATION; EXPRESSION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 17 Apr 2020 05:27 |
| Last Modified: | 17 Apr 2020 05:27 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27503 |
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