Off-target inhibition of PKA RII by crizotinib leads to reduced hERG expression and acquired QT prolongation.
Bingyu Zheng1, Yue Zhu1, Jingcheng Chen2
1Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
Heart Rhythm
|June 26, 2026
Summary
Crizotinib prolongs the QT interval and increases arrhythmia risk by suppressing cAMP-PKA signaling and reducing KCNH2. Activating this pathway can mitigate these effects, offering a potential therapeutic strategy for crizotinib-induced cardiotoxicity.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Crizotinib, a targeted therapy for non-small cell lung carcinoma, is linked to QT interval prolongation.
- Understanding the mechanisms of this cardiotoxicity is crucial for patient safety.
Purpose of the Study:
- To investigate the arrhythmogenic mechanisms behind crizotinib-induced QT prolongation.
- To identify potential therapeutic targets for mitigating crizotinib cardiotoxicity.
Main Methods:
- In vivo electrophysiological studies in guinea pigs and in vitro studies using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
- Phosphoproteomic profiling to identify signaling pathways affected by crizotinib.
- Validation using immunoblotting, kinase assays, and pharmacological rescue experiments.
Main Results:
- Crizotinib administration prolonged QT intervals and increased ventricular arrhythmia inducibility in guinea pigs.
- In iPSC-CMs, crizotinib prolonged action potential duration and reduced KCNH2 (hERG) protein levels.
- Crizotinib suppressed cAMP-PKA signaling, leading to reduced hERG expression and function.
- Forskolin-induced activation of cAMP signaling reversed these effects in vitro and in vivo.
Conclusions:
- Crizotinib induces QT prolongation and arrhythmias by suppressing cAMP-PKA signaling, which downregulates KCNH2.
- Pharmacological enhancement of cAMP signaling can counteract crizotinib-induced cardiotoxicity.
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