Related Experiment Video

Updated: Jun 28, 2026

Hybrid Cell Analysis System to Assess Structural and Contractile Changes of Human iPSC-Derived Cardiomyocytes for Preclinical Cardiac Risk Evaluation
08:03

Hybrid Cell Analysis System to Assess Structural and Contractile Changes of Human iPSC-Derived Cardiomyocytes for Preclinical Cardiac Risk Evaluation

Published on: October 20, 2022

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
PubMed
Abstract

Insights

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.
Keywords:
Acquired long QTCrizotinibPhosphoproteomicsVentricular arrhythmiashERG

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