Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL

• Published in: Nature chemical biology Vol. 15; no. 3; pp. 232 - 240
• Main Authors: Schmidl, Christian, Vladimer, Gregory I., Rendeiro, André F., Schnabl, Susanne, Krausgruber, Thomas, Taubert, Christina, Krall, Nikolaus, Pemovska, Tea, Araghi, Mohammad, Snijder, Berend, Hubmann, Rainer, Ringler, Anna, Runggatscher, Kathrin, Demirtas, Dita, de la Fuente, Oscar Lopez, Hilgarth, Martin, Skrabs, Cathrin, Porpaczy, Edit, Gruber, Michaela, Hoermann, Gregor, Kubicek, Stefan, Staber, Philipp B., Shehata, Medhat, Superti-Furga, Giulio, Jäger, Ulrich, Bock, Christoph
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2019; Nature Publishing Group
• Subjects: 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
• ISSN: 1552-4450; 1552-4469; 1552-4469
• DOI: 10.1038/s41589-018-0205-2

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.