title: A target-disease network model of second-generation BCR-ABL inhibitor action in Ph+ ALL.
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.
authors.affiliation: CeMM - Research Center, Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rix
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.forename: Katharina
authors.initials: K
authors.lastname: Blatt
authors.forename: Manuela
authors.initials: M
authors.lastname: Gridling
authors.forename: Lily L
authors.initials: LL
authors.lastname: Remsing Rix
authors.forename: Katja
authors.initials: K
authors.lastname: Parapatics
authors.forename: Sabine
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Burkard
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jäger
authors.forename: Junia V
authors.initials: JV
authors.lastname: Melo
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D060066:Protein Interaction Maps / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D040901:Proteomics; D049490:Systems Biology
chemical_list: D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl