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|a Winter, Georg E
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|a Massachusetts Institute of Technology. Department of Biological Engineering
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|a Koch Institute for Integrative Cancer Research at MIT
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|a Carlson, Scott M.
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|a White, Forest M.
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|a Rix, Uwe
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|a Gleixner, Karoline V
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|a Grebien, Florian
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|a Gridling, Manuela
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|a Breitwieser, Florian P
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|a Bilban, Martin
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|a Colinge, Jacques
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|a Valent, Peter
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|a Bennett, Keiryn L
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|a Superti-Furga, Giulio
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|a Carlson, Scott M.
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|a White, Forest M.
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|a Muller, Andre C
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|a Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML
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|b Nature Publishing Group,
|c 2014-08-26T12:05:55Z.
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|z Get fulltext
|u http://hdl.handle.net/1721.1/89043
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|a Occurrence of the BCR-ABL[superscript 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[superscript 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[superscript T315I] CML cells on c-Myc through nonobvious off targets.
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|a Article
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|t Nature Chemical Biology
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