Abstract
BackgroundSinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We investigated whether crizotinib could influence heart rate (HR) through direct cardiac effects.MethodsThe direct effect of crizotinib on HR was studied using ECG analysis of Langendorff-perfused mouse hearts. The whole-cell patch clamp technique was used to measure the effects of crizotinib on the hyperpolarization-activated funny current, If, in mouse sinoatrial node cells (SANCs) and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) activity in HEK-293 cells stably expressing human HCN4.ResultsCrizotinib resulted in a dose-dependent reduction in HR in isolated intact mouse hearts with a half maximal inhibitory concentration (IC50) of 1.7 ± 0.4 μmol/L. Because ECG analysis revealed that crizotinib (0–5 μmol/L) resulted in significant reductions in HR in isolated mouse hearts without changes in PR, QRS, or QT intervals, we performed whole-cell patch clamp recordings of SANCs which showed that crizotinib inhibited If which regulates cardiac pacemaker activity. Crizotinib resulted in diminished current density of HCN4, the major molecular determinant of If, with an IC50 of 1.4 ± 0.3 μmol/L. Crizotinib also slowed HCN4 activation and shifted the activation curve to the left towards more hyperpolarized potentials.ConclusionsOur results suggest that crizotinib’s effects on HCN4 channels play a significant role in mediating its observed effects on HR.
Highlights
Sinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC)
Crizotinib results in a dose dependent decrease in heart rate (HR) Mouse hearts were isolated and perfused as described in Methods in order to determine the direct effect of crizotinib on HR: excluding potential indirect cardiac effects that could be seen in an intact animal such as those mediated by metabolic hormones or neurohormonal activation
Because ECG analysis of isolated mouse hearts revealed that crizotinib resulted in a decrease in HR in isolated intact mouse hearts without changes in PR, QRS, or QTC intervals, similar to as observed in human subjects [4, 6], we investigated whether crizotinib exerted its effects on HR through inhibition of the hyperpolarization-activated funny current, If, in sinoatrial node cells (SANCs) which regulates cardiac pacemaker activity and HR
Summary
Sinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Crizotinib is a first-in-class, orally available multitargeted receptor tyrosine kinase (RTK) inhibitor for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) that is locally advanced or metastatic [1]. A decrease in HR is frequently observed in patients treated with crizotinib [5], the mechanism of the observed reduction in HR is unknown It is unclear if the decrease in HR is a direct cardiac effect since other indirect factors such as metabolic hormones and neurohormonal activity can have significant effects on HR, and crizotinib has been associated with endocrine effects such as lowering of testosterone levels in men [7, 8]. We investigated whether crizotinib could influence HR through direct cardiac effects using a combination of approaches involving intact mouse heart physiology and cellular electrophysiology
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