What is the clinical evidence from this study?

Study design: Other. Population: Crizotinib-induced QT prolongation. Intervention: Crizotinib. Primary outcome: QT interval, ventricular effective refractory periods, and ventricular arrhythmia inducibility.

What does this research mean for the field?

Crizotinib induces QT prolongation and increases susceptibility to ventricular arrhythmias by suppressing cAMP-PKA activity and downregulating KCNH2 (hERG), an effect that can be mitigated by pharmacological activation of cAMP signaling. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to investigate the mechanisms by which crizotinib induces QT prolongation and ventricular arrhythmias.

June 27, 2026Heart Rhythm0 citations

View Full Paper

Off-Target Inhibition of PKA RII by Crizotinib Leads to Reduced hERG Expression and Acquired QT Prolongation

BZBingyu ZhengJiangsu Province Hospital YZYue ZhuNanjing Medical University JCJingcheng ChenChangzhou No.2 People's Hospital

Key Result

Crizotinib prolonged the QT interval and increased susceptibility to ventricular arrhythmias by suppressing cAMP-PKA activity and downregulating KCNH2.

Key Points

This research aims to investigate the mechanisms by which crizotinib induces QT prolongation and ventricular arrhythmias.
In vivo electrophysiological studies in guinea pigs administered crizotinib for seven days.
Utilization of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to assess action potential duration after crizotinib exposure.
Phosphoproteomic profiling and validation using immunoblotting and kinase activity assays.
Crizotinib significantly prolonged the QT interval and increased ventricular arrhythmia inducibility in guinea pigs.
After 48 hours of crizotinib exposure, action potential duration at 90% repolarization was prolonged.
Activation of cAMP signaling helped mitigate the QT prolongation effects caused by crizotinib.

Structured PICO

Does crizotinib induce QT prolongation and ventricular arrhythmias through specific molecular pathways in preclinical models?

Population

Guinea pigs and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)

Intervention

Crizotinib (7-day administration in vivo, 48 hours in vitro)

Outcome

QT interval, ventricular effective refractory periods, ventricular arrhythmia inducibility, action potential duration, and molecular signaling pathways (cAMP-PKA activity, KCNH2 expression)surrogate

Crizotinib-induced QT prolongation and ventricular arrhythmia susceptibility are mediated by suppression of cAMP-PKA activity and downregulation of KCNH2, offering a potential pharmacological target for mitigation.

Abstract

BACKGROUND: Crizotinib, a tyrosine kinase inhibitor used for target therapies in non-small cell lung carcinoma, has been associated with an increased risk of QT interval prolongation. OBJECTIVE: To elucidate the arrhythmogenic mechanisms underlying crizotinib-induced QT prolongation. METHODS: In vivo electrophysiological studies were performed in guinea pigs treated with crizotinib. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were exposed to crizotinib, and action potentials were recorded. Phosphoproteomic profiling was conducted to identify downstream signaling pathways involved in crizotinib-induced repolarization abnormalities. Candidate mechanisms were validated using immunoblotting, kinase activity assays, and pharmacological rescue experiments. RESULTS: Seven-day crizotinib administration in guinea pigs significantly prolonged the QT interval, increased ventricular effective refractory periods, and enhanced ventricular arrhythmia inducibility. Crizotinib exposure for 48 hours significantly prolonged action potential duration at 90% repolarization (APD CONCLUSION: Crizotinib prolonged the QT interval and increased susceptibility to ventricular arrhythmias by suppressing cAMP-PKA activity and thereby downregulating KCNH2. Pharmacological activation of cAMP signaling mitigated crizotinib-induced acquired QT prolongation.

问 AI

Bookmark

View Full Paper

Cite This Study

Zheng et al. (Mon,) conducted a other in Crizotinib-induced QT prolongation. Crizotinib was evaluated on QT interval, ventricular effective refractory periods, and ventricular arrhythmia inducibility. Crizotinib prolonged the QT interval and increased susceptibility to ventricular arrhythmias by suppressing cAMP-PKA activity and downregulating KCNH2.

synapsesocial.com/papers/6a3f9997125782b61d865d37 https://doi.org/https://doi.org/10.1016/j.hrthm.2026.06.025

Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

问 AI

Bookmark

View Full Paper