Abstract

Alectinib is the first-line therapy for anaplastic lymphoma kinase rearranged non-small cell lung cancer globally. Sinus bradycardia, as the major adverse cardiac events of alectinib, still widely impact patient's quality of life. However, its underlying mechanism remains elusive. The aim of this study was to reveal the pathogenesis of the alectinib induced sinus bradycardia (AISB) in a rat model, including the electrophysiology alterations and the molecular mechanism. SD rats were administered alectinib (10 mg / kg / day) by gavage for 7 to 10 days to mimic the clinical AISB. 3-days alectinib treatment did not change heart rate and sinus node recovery time (SNRT) as assessed through in vivo electrophysiology study. Also, alectinib didn't influence automaticity in isolated heart or single sinus node cardiomyocytes, indicating alectinib cannot decrease sinus node function rapidly. The decreased heart rate and prolonged SNRT was found after 7-days alectinib treatment. The inducibility of atrial fibrillation was not affected under the same condition. The RNA-seq assay revealed the transcriptomic alterations in sinus node of alectinib treated rats, and the dysregulation of genes in cardiac function were observed. The decreased expression of L-type calcium channel Cacna1d was confirmed among the channel candidates identified from RNA-seq assay. Subsequently, the patch-clamp test revealed the reduction in the corresponding L-type calcium current density in 7-days alectinib treated rats. These findings revealed that the AISB was caused by the reduction in Cacna1d expression which resulted in the electro-dysfunction mediated by the suppressed I.