Abstract
Kinase Inhibitor Therapy in CML: It's What's Inside That Counts
Highlights
The paradigm-shifting clinical success of imatinib in the treatment of chronic myeloid leukemia (CML) established continuous inhibition of the BCR-ABL1 oncoprotein as a design principle for ABL1 tyrosine kinase inhibitors
Nilotinib, and ponatinib were capable of triggering apoptosis following transient exposure; neither imatinib nor DCC-2036 induced significant apoptosis following washout of concentrations up to 5 μM
Transient inhibition of BCR-ABL1 being the only requirement for commitment of CML cells to apoptosis, we found that apoptosis could be reversed under conditions involving extensive additional inhibitor washout
Summary
The paradigm-shifting clinical success of imatinib in the treatment of chronic myeloid leukemia (CML) established continuous inhibition of the BCR-ABL1 oncoprotein as a design principle for ABL1 tyrosine kinase inhibitors. Previous work by our group and others demonstrated that apoptosis commitment after potent, transient target inhibition can be recapitulated using in vitro inhibitor washout protocols [2,3,4]. We treated CML cells transiently with a panel of five clinically-relevant ABL1 tyrosine kinase inhibitors – imatinib, nilotinib, dasatinib, ponatinib (AP24534), DCC-2036 – and investigated pathways critical to drug efficacy and intracellular residence time, focusing on clinically-relevant concentrations of each drug.
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