Abstract
Occurrence of the BCR-ABL(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(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(T315I) CML cells on c-Myc through nonobvious off targets.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Compounds / pharmacology*
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects
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Benzamides / pharmacology*
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Cell Line, Tumor
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Down-Regulation / drug effects
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Drug Resistance, Neoplasm / drug effects*
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Drug Synergism
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Fusion Proteins, bcr-abl / antagonists & inhibitors
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Fusion Proteins, bcr-abl / genetics
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Imatinib Mesylate
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Mice
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Nitriles / pharmacology*
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Piperazines / pharmacology*
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Protein Kinase Inhibitors / pharmacology*
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Proteomics
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Proto-Oncogene Proteins c-myc / antagonists & inhibitors
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Proto-Oncogene Proteins c-myc / metabolism
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Pyrazoles / pharmacology*
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Pyrimidines / pharmacology*
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Quinolines / pharmacology*
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Structure-Activity Relationship
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Systems Biology
Substances
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Aniline Compounds
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Benzamides
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Nitriles
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Piperazines
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-myc
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Pyrazoles
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Pyrimidines
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Quinolines
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bosutinib
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Imatinib Mesylate
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Fusion Proteins, bcr-abl
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danusertib