Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML
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Author(s)
Winter, Georg E
Rix, Uwe
Gleixner, Karoline V
Grebien, Florian
Gridling, Manuela
Breitwieser, Florian P
Bilban, Martin
Colinge, Jacques
Valent, Peter
Bennett, Keiryn L
Date Issued
September 2012
Journal
Nature Chemical Biology
Publisher
Nature Publishing Group
Citation
Winter, Georg E, Uwe Rix, Scott M Carlson, Karoline V Gleixner, Florian Grebien, Manuela Gridling, Andre C Muller, et al. “Systems-Pharmacology Dissection of a Drug Synergy in Imatinib-Resistant CML.” Nat Chem Biol 8, no. 11 (September 30, 2012): 905–912.
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Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1038/nchembio.1085
