Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors
  • Agammaglobulinaemia Tyrosine Kinase / metabolism*
  • Cell Cycle Proteins / metabolism
  • Chromatin / physiology
  • Drug Combinations
  • Drug Resistance, Neoplasm / genetics
  • Epigenesis, Genetic / genetics
  • Epigenomics / methods
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Protein Kinase Inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Protein-Tyrosine Kinases / physiology
  • Proto-Oncogene Proteins / metabolism
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Signal Transduction
  • Single-Cell Analysis / methods
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Cell Cycle Proteins
  • Chromatin
  • Drug Combinations
  • PCI 32765
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyrazoles
  • Pyrimidines
  • TOR Serine-Threonine Kinases
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1