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

• Main Authors: Winter, Georg E (Author), Rix, Uwe (Author), Gleixner, Karoline V (Author), Grebien, Florian (Author), Gridling, Manuela (Author), Breitwieser, Florian P (Author), Bilban, Martin (Author), Colinge, Jacques (Author), Valent, Peter (Author), Bennett, Keiryn L (Author), Superti-Furga, Giulio (Author), Carlson, Scott M. (Contributor), White, Forest M. (Contributor), Muller, Andre C (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: Nature Publishing Group, 2014-08-26T12:05:55Z.
• Subjects: Article
• Online Access: Get fulltext

 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.