Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL
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 vul...
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| Published in | Nature chemical biology Vol. 15; no. 3; pp. 232 - 240 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Nature Publishing Group US
01.03.2019
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1552-4450 1552-4469 1552-4469 |
| DOI | 10.1038/s41589-018-0205-2 |
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| 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.
Epigenome profiling in combination with imaging-based chemosensitivity and integrative bioinformatic analysis establishes a method for detecting therapy-induced vulnerabilities, as shown here for ibrutinib-treated chronic lymphocytic leukemia. |
|---|---|
| AbstractList | The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially
improved therapeutic options for chronic lymphocytic leukemia (CLL). While
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. 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. 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. Epigenome profiling in combination with imaging-based chemosensitivity and integrative bioinformatic analysis establishes a method for detecting therapy-induced vulnerabilities, as shown here for ibrutinib-treated chronic lymphocytic leukemia. 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.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. 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. 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.Epigenome profiling in combination with imaging-based chemosensitivity and integrative bioinformatic analysis establishes a method for detecting therapy-induced vulnerabilities, as shown here for ibrutinib-treated chronic lymphocytic leukemia. |
| Author | Kubicek, Stefan Bock, Christoph Staber, Philipp B. de la Fuente, Oscar Lopez Vladimer, Gregory I. Shehata, Medhat Demirtas, Dita Snijder, Berend Hubmann, Rainer Schnabl, Susanne Runggatscher, Kathrin Pemovska, Tea Araghi, Mohammad Ringler, Anna Taubert, Christina Hilgarth, Martin Schmidl, Christian Krausgruber, Thomas Superti-Furga, Giulio Porpaczy, Edit Hoermann, Gregor Skrabs, Cathrin Rendeiro, André F. Gruber, Michaela Krall, Nikolaus Jäger, Ulrich |
| AuthorAffiliation | 3 Allcyte GmbH, Vienna, Austria 1 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria 2 Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria 5 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria 4 Christian Doppler Laboratory for Chemical Epigenetics and Anti-Infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria 6 Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria 8 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria 7 Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, Germany |
| AuthorAffiliation_xml | – name: 3 Allcyte GmbH, Vienna, Austria – name: 6 Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria – name: 5 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria – name: 8 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria – name: 2 Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria – name: 7 Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, Germany – name: 1 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria – name: 4 Christian Doppler Laboratory for Chemical Epigenetics and Anti-Infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria |
| Author_xml | – sequence: 1 givenname: Christian orcidid: 0000-0002-0522-202X surname: Schmidl fullname: Schmidl, Christian organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Regensburg Centre for Interventional Immunology and University Medical Center of Regensburg – sequence: 2 givenname: Gregory I. orcidid: 0000-0003-4205-7585 surname: Vladimer fullname: Vladimer, Gregory I. organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Allcyte GmbH – sequence: 3 givenname: André F. orcidid: 0000-0001-9362-5373 surname: Rendeiro fullname: Rendeiro, André F. organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences – sequence: 4 givenname: Susanne surname: Schnabl fullname: Schnabl, Susanne organization: Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna – sequence: 5 givenname: Thomas surname: 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Medicine of the Austrian Academy of Sciences, Department of Biology, Institute of Molecular Systems Biology, ETH Zurich – sequence: 11 givenname: Rainer surname: Hubmann fullname: Hubmann, Rainer organization: Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna – sequence: 12 givenname: Anna surname: Ringler fullname: Ringler, Anna organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Christian Doppler Laboratory for Chemical Epigenetics and Anti-Infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences – sequence: 13 givenname: Kathrin surname: Runggatscher fullname: Runggatscher, Kathrin organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Christian Doppler Laboratory for Chemical Epigenetics and Anti-Infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences – sequence: 14 givenname: Dita surname: Demirtas fullname: Demirtas, Dita organization: Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna – sequence: 15 givenname: Oscar Lopez surname: de la Fuente fullname: de la Fuente, Oscar Lopez organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Allcyte GmbH – sequence: 16 givenname: Martin surname: Hilgarth fullname: Hilgarth, Martin organization: Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna – sequence: 17 givenname: Cathrin surname: Skrabs fullname: Skrabs, Cathrin organization: Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna – sequence: 18 givenname: Edit surname: Porpaczy fullname: Porpaczy, Edit organization: Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna – sequence: 19 givenname: Michaela surname: Gruber fullname: Gruber, Michaela organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna – sequence: 20 givenname: Gregor surname: Hoermann fullname: Hoermann, Gregor organization: Department of Laboratory Medicine, Medical University of Vienna – sequence: 21 givenname: Stefan orcidid: 0000-0003-0855-8343 surname: Kubicek fullname: Kubicek, Stefan organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Christian Doppler Laboratory for Chemical Epigenetics and Anti-Infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences – sequence: 22 givenname: Philipp B. surname: Staber fullname: Staber, Philipp B. organization: Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna – sequence: 23 givenname: Medhat surname: Shehata fullname: Shehata, Medhat organization: Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna – sequence: 24 givenname: Giulio orcidid: 0000-0002-0570-1768 surname: Superti-Furga fullname: Superti-Furga, Giulio organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Center for Physiology and Pharmacology, Medical University of Vienna – sequence: 25 givenname: Ulrich surname: Jäger fullname: Jäger, Ulrich organization: Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna – sequence: 26 givenname: Christoph orcidid: 0000-0001-6091-3088 surname: Bock fullname: Bock, Christoph email: cbock@cemm.oeaw.ac.at organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Department of Laboratory Medicine, Medical University of Vienna, Max Planck Institute for Informatics, Saarland Informatics Campus, Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30692684$$D View this record in MEDLINE/PubMed |
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| Copyright | The Author(s), under exclusive licence to Springer Nature America, Inc. 2019 2019© The Author(s), under exclusive licence to Springer Nature America, Inc. 2019 |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Co-first author / These authors contributed equally to this work Current address: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland Current address: Allcyte GmbH, Vienna, Austria Current address: Regensburg Centre for Interventional Immunology and University Medical Center of Regensburg, Regensburg, Germany. Co-last author / These authors jointly directed this work |
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| Snippet | The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib... The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). While ibrutinib is... |
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| SubjectTerms | 631/114 631/1647/328 631/337/100 631/553 631/67/1059 Adenine - analogs & derivatives Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors Agammaglobulinaemia Tyrosine Kinase - metabolism Biochemical Engineering Biochemistry Bioorganic Chemistry Bruton's tyrosine kinase Cell Biology Cell Cycle Proteins - metabolism Chemistry Chemistry and Materials Science Chemistry/Food Science Chromatin Chromatin - physiology Chronic lymphocytic leukemia Data integration Drug Combinations Drug Resistance, Neoplasm - genetics Enzyme inhibitors Epigenesis, Genetic - genetics Epigenetics Epigenomics - methods Gene regulation Humans Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy Leukemia, Lymphocytic, Chronic, B-Cell - genetics Lymphatic leukemia Patients Pharmacology Piperidines Polo-Like Kinase 1 Proteasomes Protein Kinase Inhibitors Protein Serine-Threonine Kinases - metabolism Protein-tyrosine kinase Protein-Tyrosine Kinases - metabolism Protein-Tyrosine Kinases - physiology Proto-Oncogene Proteins - metabolism Pyrazoles - pharmacology Pyrimidines - pharmacology Signal Transduction Single-Cell Analysis - methods TOR protein TOR Serine-Threonine Kinases - metabolism Tyrosine |
| Title | Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL |
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