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Gewählte Publikation:

Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2012

AutorInnen: Winter, GE; Rix, U; Carlson, SM; Gleixner, KV; Grebien, F; Gridling, M; Müller, AC; Breitwieser, FP; Bilban, M; Colinge, J; Valent, P; Bennett, KL; White, FM; Superti-Furga, G

Titel: Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML.

Quelle: Nat Chem Biol. 2012; 8(11):905-912



Autor/innen der Vetmeduni Vienna:

Grebien Florian

Diese Publikation wurde nicht im Namen der Vetmeduni Vienna erstellt und ist deshalb ausschließlich der persönlichen Publikationsliste des/der Autors/Autorin zugeordnet!


Abstract:
Occurrence of the BCR-ABL(T315I) gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL(T315I). To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL(T315I) CML cells on c-Myc through nonobvious off targets.

Keywords Pubmed: Aniline Compounds/pharmacology*
Animals
Antineoplastic Combined Chemotherapy Protocols/pharmacology*
Apoptosis/drug effects
Benzamides/pharmacology*
Cell Line, Tumor
Cell Survival/drug effects
Dose-Response Relationship, Drug
Down-Regulation/drug effects
Drug Resistance, Neoplasm/drug effects*
Drug Synergism
Fusion Proteins, bcr-abl/antagonists & inhibitors
Fusion Proteins, bcr-abl/genetics
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
Mice
Nitriles/pharmacology*
Piperazines/pharmacology*
Protein Kinase Inhibitors/pharmacology*
Proteomics
Proto-Oncogene Proteins c-myc/antagonists & inhibitors
Proto-Oncogene Proteins c-myc/metabolism
Pyrazoles/pharmacology*
Pyrimidines/pharmacology*
Quinolines/pharmacology*
Structure-Activity Relationship
Systems Biology


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