Threshold Levels of ABL Tyrosine Kinase Inhibitors Retained in Chronic Myeloid Leukemia Cells Determine Their Commitment to Apoptosis

摘要: The imatinib paradigm in chronic myeloid leukemia (CML) established continuous BCR-ABL inhibition as a design principle for ABL tyrosine kinase inhibitors (TKIs). However, clinical responses seen patients treated with the TKI dasatinib despite its much shorter plasma half-life and apparent rapid restoration of signaling activity following once-daily dosing suggested acute, potent may be sufficient to irrevocably commit CML cells apoptosis. To determine specific requirements TKI-induced cell death panel clinically important TKIs (imatinib, nilotinib, dasatinib, ponatinib, DCC-2036), we interrogated response lines primary acute drug exposure using intracellular FACS immunoblot analyses signaling, apoptosis measurements, liquid chromatography/tandem mass spectrometry levels, biochemical dissociation studies. Importantly, significant stores were detected washout, levels which tracked onset incomplete return particularly pSTAT5, baseline. Among tested, ponatinib demonstrated most robust capacity apoptotic commitment showing sustained suppression even at low extensive consistent high-affinity binding slow from kinase. Together, our findings suggest requires protracted mediated by retention above quantifiable threshold. These studies refine understanding highlight parameters therapeutic other malignancies.