Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/93363
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dc.contributor.author | Rix, U. | - |
dc.contributor.author | Colinge, J. | - |
dc.contributor.author | Blatt, K. | - |
dc.contributor.author | Gridling, M. | - |
dc.contributor.author | Remsing Rix, L. | - |
dc.contributor.author | Parapatics, K. | - |
dc.contributor.author | Cerny-Reiterer, S. | - |
dc.contributor.author | Burkard, T. | - |
dc.contributor.author | Jäger, U. | - |
dc.contributor.author | Melo, J. | - |
dc.contributor.author | Bennett, K. | - |
dc.contributor.author | Valent, P. | - |
dc.contributor.author | Superti-Furga, G. | - |
dc.contributor.editor | Bendall, L. | - |
dc.date.issued | 2013 | - |
dc.identifier.citation | PLoS One, 2013; 8(10):e77155-1-e77155-14 | - |
dc.identifier.issn | 1932-6203 | - |
dc.identifier.issn | 1932-6203 | - |
dc.identifier.uri | http://hdl.handle.net/2440/93363 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | Uwe Rix, a, Jacques Colinge, Katharina Blatt, Manuela Gridling, Lily L. Remsing Rix, a, Katja Parapatics, Sabine Cerny-Reiterer, Thomas R. Burkard, Ulrich Jäger, Junia V. Melo, Keiryn L. Bennett, Peter Valent, Giulio Superti-Furga | - |
dc.language.iso | en | - |
dc.publisher | Public Library of Science | - |
dc.rights | © 2013 Rix et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | - |
dc.source.uri | http://dx.doi.org/10.1371/journal.pone.0077155 | - |
dc.subject | Molecular Targeted Therapy | - |
dc.title | A target-disease network model of second-generation BCR-ABL inhibitor action in Ph+ ALL | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1371/journal.pone.0077155 | - |
pubs.publication-status | Published | - |
Appears in Collections: | Aurora harvest 2 Medicine publications |
Files in This Item:
File | Description | Size | Format | |
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hdl_93363.pdf | Published version | 1.43 MB | Adobe PDF | View/Open |
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