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Nat Chem Biol. 2019 Mar;15(3):232-240. doi: 10.1038/s41589-018-0205-2. Epub 2019 Jan 28.

Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
2
Regensburg Centre for Interventional Immunology and University Medical Center of Regensburg, Regensburg, Germany.
3
Allcyte GmbH, Vienna, Austria.
4
Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
5
Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
6
Christian Doppler Laboratory for Chemical Epigenetics and Anti-Infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
7
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
8
Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
9
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. cbock@cemm.oeaw.ac.at.
10
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. cbock@cemm.oeaw.ac.at.
11
Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, Germany. cbock@cemm.oeaw.ac.at.
12
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria. cbock@cemm.oeaw.ac.at.

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.

PMID:
30692684
DOI:
10.1038/s41589-018-0205-2

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