التفاصيل البيبلوغرافية
| العنوان: |
Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML. |
| المؤلفون: |
Winter, Georg E, Rix, Uwe, Carlson, Scott M, Gleixner, Karoline V, Grebien, Florian, Gridling, Manuela, Müller, André C, Breitwieser, Florian P, Bilban, Martin, Colinge, Jacques, Valent, Peter, Bennett, Keiryn L, White, Forest M, Superti-Furga, Giulio |
| المصدر: |
Nature Chemical Biology; Nov2012, Vol. 8 Issue 11, p905-912, 8p, 5 Graphs |
| مصطلحات موضوعية: |
DRUG synergism, IMATINIB, CHRONIC myeloid leukemia, DRUG resistance in cancer cells, GENETIC mutation, MITOGEN-activated protein kinases, PROTEOMICS |
| مستخلص: |
Occurrence of the BCR-ABLT315I 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-ABLT315I. 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-ABLT315I CML cells on c-Myc through nonobvious off targets. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
