CeMM: Winter et al.: Understanding off-target synergy for kinase inhibitors against drug resistant CML

The off-target activity of two drugs that target an oncogene, called BCR-ABL, explains their synergistic and selective ability to induce cell death in gatekeeper mutated chronic myeloid leukemia (CML) cells. The findings of scientists in the research groups of CeMM Scientific Director Giulio Superti-Furga, Keiryn L. Bennett (Mass Spectrometry), and Jacques Colinge (Bioinformatics) together with research group of Forest M. White, Massachusetts Institute of Technology, Cambridge, Massachusetts and colleagues of the Medical University of Vienna, esp. Peter Valent and Martin Bilban have been published online on September 30th, 2012, in Nature Chemical Biology.

The presence of BCR-ABL oncogene is a hallmark for CML, and targeted kinase inhibitors, have yielded impressive clinical treatment results for patients. Mutation of BCR-ABL at the so-called gatekeeper residue of BCR-ABL renders these cancers resistant to all drugs currently approved for clinical use. Identifying new strategies to treat CML with these mutations and understanding the biology underlying their effectiveness is thus a priority.

Giulio Superti-Furga and colleagues report that the combination of two BCR-ABL inhibitor drugs, danusertib and bosutinib, is selectively effective against gatekeeper mutation-positive CML, independent of their activity against their primary target, BCR-ABL. The authors combine three approaches (transcriptomics, phosphoproteomics and chemoproteomics) to identify MAP kinases as the off-target hits responsible for the biological synergy. They also provide evidence that changes in the activity of the oncogene c-MYC, acting downstream of MAPKs, as the critical point of convergence that explains the activity of the drug combination.
The study was supported by the "GEN-AU" initiative of the Austrian Federal Ministery for Science and Research and the Austrian Science Fund FWF.

Georg E. Winter1#, Uwe Rix1#§, Scott M. Carlson2†, Karoline V. Gleixner4, Florian Grebien1, Manuela Gridling1, André C  Müller1, Florian P. Breitwieser1, Martin Bilban3, Jacques Colinge1, Peter Valent4,5, Keiryn L. Bennett1, Forest M. White2 and Giulio Superti-Furga1. Systems-pharmacology dissection of a drug synergy in imatinib resistant CML. Nature Chemical Biology.2012 Sept 30. DOI: 10.1038/NChemBio.1085.

1CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; 2Department of Biological Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts,  USA; 3Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria 4Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; 5Ludwig Boltzmann Cluster Oncology, Vienna, Austria

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