The Myocyte-Damaging Effects of the BCR-ABL1-Targeted Tyrosine Kinase Inhibitors Increase with Potency and Decrease with Specificity

摘要

Five clinically approved BCR-ABL1-targeted tyrosine kinase inhibitors (bosutinib, dasatinib, imatinib, nilotinib, and ponatinib) used for treating chronic myelogenous leukemia have been studied in a neonatal rat myocyte model for their relative ability to induce myocyte damage. This was done in order to determine if kinase inhibitor-induced myocyte damage was a consequence of inhibiting ABL1 (on-target effects), or due to a lack of kinase selectivity (off-target effects) since previous studies have come up with conflicting conclusions about whether imatinib-induced cardiotoxicity results directly from inhibition of ABL1. The most specific and least potent inhibitors, imatinib and nilotinib, induced the least myocyte damage, while the least specific and most potent inhibitors, ponatinib and dasatinib, induced the most damage. Inhibitor-induced myocyte damage also correlated with clinically observed cardiovascular toxicity. Growth inhibition of the erythroleukemic K562 human cell line with a constitutively active BCR-ABL1 kinase was negatively correlated with inhibitor-induced myocyte damage, which suggests that inhibition of ABL1 causes myocyte damage. Myocyte damage was also negatively correlated with inhibitor dissociation binding constants and with inhibition of enzymatic ABL1 kinase activity. Myocyte damage was also positively correlated with two measures of inhibitor selectivity, which suggests that a lack of inhibitor selectivity is responsible for myocyte damage. In conclusion, myocyte damage, and thus the cardiovascular toxicity of the BCR-ABL1-targeted tyrosine kinase inhibitors, is due to direct inhibition of ABL1 and/or their lack of inhibitor selectivity.