A target-disease network model of second-generation BCR-ABL inhibitor action in Ph+ ALL

PLoS One. 2013 Oct 10;8(10):e77155. doi: 10.1371/journal.pone.0077155. eCollection 2013.


Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is in part driven by the tyrosine kinase bcr-abl, but imatinib does not produce long-term remission. Therefore, second-generation ABL inhibitors are currently in clinical investigation. Considering different target specificities and the pronounced genetic heterogeneity of Ph+ ALL, which contributes to the aggressiveness of the disease, drug candidates should be evaluated with regard to their effects on the entire Ph+ ALL-specific signaling network. Here, we applied an integrated experimental and computational approach that allowed us to estimate the differential impact of the bcr-abl inhibitors nilotinib, dasatinib, Bosutinib and Bafetinib. First, we determined drug-protein interactions in Ph+ ALL cell lines by chemical proteomics. We then mapped those interactions along with known genetic lesions onto public protein-protein interactions. Computation of global scores through correlation of target affinity, network topology, and distance to disease-relevant nodes assigned the highest impact to dasatinib, which was subsequently confirmed by proliferation assays. In future, combination of patient-specific genomic information with detailed drug target knowledge and network-based computational analysis should allow for an accurate and individualized prediction of therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Humans
  • Models, Biological*
  • Molecular Targeted Therapy
  • Philadelphia Chromosome*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein Interaction Maps / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proteomics*
  • Systems Biology*


  • Protein Kinase Inhibitors
  • Fusion Proteins, bcr-abl

Grant support

This study was supported by the Austrian federal ministry for science and research bmwf under the GEN-AU program projects PLACEBO and BIN III (GZ BMWF-70.081/0018-II/1a/2008, FFG project numbers 820961 and 820962), the Austrian Science Fund (FWF; P18737-B11) and the NIHR Biomedical Research Centre Funding Scheme, UK. CeMM is supported by the Austrian Academy of Sciences (ÖAW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.