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

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

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1
CeMM - Research Center, Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Abstract

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.

PMID:
24130846
PMCID:
PMC3795025
DOI:
10.1371/journal.pone.0077155
[Indexed for MEDLINE]
Free PMC Article
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