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.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Chromatin/physiology , Drug Combinations , Drug Resistance, Neoplasm/genetics , Epigenesis, Genetic/genetics , Epigenomics/methods , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Piperidines , 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 , Polo-Like Kinase 1ABSTRACT
Small-molecule drugs may complement antibody-based therapies in an immune-oncology setting, yet systematic methods for the identification and characterization of the immunomodulatory properties of these entities are lacking. We surveyed the immumomodulatory potential of 1,402 small chemical molecules, as defined by their ability to alter the cell-cell interactions among peripheral mononuclear leukocytes ex vivo, using automated microscopy and population-wide single-cell image analysis. Unexpectedly, â¼10% of the agents tested affected these cell-cell interactions differentially. The results accurately recapitulated known immunomodulatory drug classes and revealed several clinically approved drugs that unexpectedly harbor the ability to modulate the immune system, which could potentially contribute to their physiological mechanism of action. For instance, the kinase inhibitor crizotinib promoted T cell interactions with monocytes, as well as with cancer cells, through inhibition of the receptor tyrosine kinase MSTR1 and subsequent upregulation of the expression of major histocompatibility complex molecules. The approach offers an attractive platform for the personalized identification and characterization of immunomodulatory therapeutics.
