2. Academic Validation
  3. Osimertinib induces reversible cardiac dysfunction through the GATA4-MYLK3-MYL2 axis

Osimertinib induces reversible cardiac dysfunction through the GATA4-MYLK3-MYL2 axis

  • Eur Heart J. 2025 Dec 3:ehaf813. doi: 10.1093/eurheartj/ehaf813.
Kai Zhang 1 2 3,  Alyssa Ayala 3,  Ignacio Norambuena-Soto 1,  Vertica Agnihotri 3,  Tao Shu 4,  Christian Nenninger 3,  Yin Wang 1 3,  Brittany Echevarria 3,  Joel Aboagye 5,  Katie Huang 1 6,  Jenaro Espitia-Corredor 1,  Xiwei Wu 7,  Zhen B Chen 8,  Yingfeng Deng 1,  J Jefferson P Perry 9,  Dan J Raz 10,  Huaxiao Yang 5,  Paul Cheng 11,  Guosheng Fu 2,  Zhao V Wang 1,  June-Wha Rhee 3
Affiliations

Affiliations

  • 1 Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
  • 2 Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 3 Division of Cardiology, Department of Medicine, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
  • 4 Integrative Genomics Shared Resource, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • 5 Department of Biomedical Engineering, University of North Texas, Denton, TX 76205, USA.
  • 6 Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA 95616, USA.
  • 7 Department of Computational and Quantitative Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
  • 8 Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • 9 Department of Molecular Diagnostics and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
  • 10 Department of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • 11 Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
PMID: 41330421 DOI: 10.1093/eurheartj/ehaf813
Abstract

Background and aims: Osimertinib is a third-generation tyrosine kinase inhibitor targeting activating mutations of epidermal growth factor receptor with remarkable therapeutic efficacy against non-small cell lung carcinoma. However, its use has been limited by associated cardiotoxicity, primarily with heart failure. Herein, this study aims to better understand the mechanisms underlying osimertinib cardiotoxicity and explore cardioprotective strategies.

Methods: This study leverages an in vitro model of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and a clinically relevant in vivo mouse model of osimertinib cardiotoxicity by co-employing transverse aortic constriction to mimic haemodynamic stress in Cancer patients.

Results: Osimertinib treatment leads to significant contractile dysfunction in mice without cell death, inflammation, or fibrosis. By leveraging single-nucleus RNA Sequencing of mouse heart tissues and in vitro assays of human iPSC-CMs, the study reveals significant downregulation of MYLK3 and a subsequent decrease in MYL2 phosphorylation with marked sarcomere disarray as the main mechanism of osimertinib cardiotoxicity. GATA4 is further identified as a putative target of osimertinib, connecting its decreased phosphorylation to repressed MYLK3 transcription. The reversibility of osimertinib-induced cardiac dysfunction upon discontinuation of osimertinib treatment supports the hypothesis that transient sarcomere disruption, rather than permanent cellular damage, serves as the key underlying mechanism. Finally, the Myosin activator omecamtiv is shown to be effective in preventing osimertinib cardiotoxicity.

Conclusions: These findings suggest that osimertinib causes reversible cardiac dysfunction by disrupting MYL2 phosphorylation via GATA4 dephosphorylation-mediated suppression of MYLK3 and highlight the potential of Myosin activation as a preventive or rescue strategy for osimertinib cardiotoxicity.

Keywords

Cardiotoxicity; Contractility; GATA binding protein 4; Heart failure; Myosin light chain 2; Myosin light chain kinase 3; Osimertinib; Sarcomere; Tyrosine kinase inhibitor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15772
    99.96%, Mutant-Selective EGFR Inhibitor