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- Title
A Target-Disease Network Model of Second-Generation BCR-ABL Inhibitor Action in Ph+ ALL.
- Authors
Rix, Uwe; Colinge, Jacques; Blatt, Katharina; Gridling, Manuela; Remsing Rix, Lily L.; Parapatics, Katja; Cerny-Reiterer, Sabine; Burkard, Thomas R.; Jäger, Ulrich; Melo, Junia V.; Bennett, Keiryn L.; Valent, Peter; Superti-Furga, Giulio
- 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.
- Subjects
LYMPHOBLASTIC leukemia; PROTEIN-tyrosine kinases; IMATINIB; PROTEIN-drug interactions; CELLULAR signal transduction; PROTEOMICS; PROTEIN-protein interactions; NILOTINIB
- Publication
PLoS ONE, 2013, Vol 8, Issue 10, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0077155