Alectinib is a highly selective tyrosine kinase inhibitor (TKI). It has been approved by over 80 countries for the current first-line therapy of anaplastic lymphoma kinase (ALK) rearranged non-small-cell lung cancer (NSCLC) (Paik and Dhillon, 2018). As the second generation of ALK-TKI, Alectinib has dramatic efficacy in ALK rearranged NSCLC which constitutes 3 %–7 % of all NSCLC cases, alongside an outstanding safety profile (Chia et al., 2014; Pikor et al., 2013; Camidge et al., 2019). Nonetheless, the adverse cardiac events still limited alectinib application and compromise patients' quality of life.

Cardiac arrhythmia is one of the most common adverse cardiac events in patients undergoing the treatment of tyrosine kinase inhibitors (TKIs) (Shyam et al., 2023). The other manifestations include cardiac structure changes, thromboembolism and heart dysfunction (Jin et al., 2020; Pruis et al., 2022). Notably, different TKIs elicit distinct effects on cardiac rhythm. Bruton's tyrosine kinase inhibitors are associated with atrial fibrillation (AF) and a shortened QT corrected interval (QTc) (Xiao et al., 2020; Pineda-Gayoso et al., 2020; Salem et al., 2019). Conversely, vascular endothelial growth factor receptor-TKIs and epidermal growth factor receptor-TKIs often result in QTc prolongation (Díaz-Serrano et al., 2018; Zang et al., 2012; Shah et al., 2013). Unlike other TKIs, ALK-TKIs only cause sinus bradycardia but not atrial or ventricular arrhythmia (Pruis et al., 2022; Yuan et al., 2023; Morcos et al., 2017). In various clinical studies of alectinib, median heart rate decreased by 11–17 beats per minute (bpm). In some cases, dose reduction and pacemaker implantation was needed due to the severe bradycardia (Pruis et al., 2022; Yuan et al., 2023). Therefore, elucidating the mechanisms underlying alectinib induced sinus bradycardia (AISB) not only holds promise for optimizing patient care in those receiving alectinib but also offers insights into the molecular mechanism underlying the arrhythmia caused by TKIs.

The sinus node functions by generating and propagating action potentials from its leading pacemaking area. This process is precisely governed by a variety of ion currents, including the funny current (If), T-type and L-type calcium current (ICaT and ICaL) (Mangoni et al., 2003, 2006; DiFrancesco, 2010). Dysfunction in any of these channels usually causes sinus node dysfunction or other kinds of cardiac arrhythmias, which are termed ‘channelopathy’ (Yeh et al., 2009; Hennis et al., 2024; Van et al., 2023). Despite the fact that mutations or dysfunctions in non-channel proteins may critically contribute to arrhythmias, their effects often manifest by influencing ion channel activity (Liu et al., 2021; Kapoor et al., 2013). Thus, studying the electrophysiological dysfunction and its underlying ion-channels alteration is essential for understanding the pathogenesis of AISB.

To date, the pathogenesis of AISB has remained elusive. In the present study, we investigated the electrophysiology alterations and the underlying molecular basis in a rat model mimicking clinical alectinib treatment. Our objective is to reveal the pathogenesis of AISB and ultimately improve the life quality of patients undergoing alectinib treatment.