2. Academic Validation
  3. Functional in vitro assessment of the HER2 Ile655Val variant on trastuzumab-induced cardiotoxicity in human cardiomyocytes

Functional in vitro assessment of the HER2 Ile655Val variant on trastuzumab-induced cardiotoxicity in human cardiomyocytes

  • Eur J Pharmacol. 2026 Jan 20:1012:178484. doi: 10.1016/j.ejphar.2025.178484.
Ana Pozo-Agundo 1,  Sonia García-Rodríguez 2,  Alba Antúnez-Rodríguez 3,  Lucía Chica-Redecillas 4,  Romina Beatriz Cejas 5,  Davi Lyra-Leite 6,  Patricia Porras-Quesada 7,  Javier Gómez-Sánchez 8,  Benito Mirón-Pozo 9,  María Jesús Álvarez-Cubero 10,  Paul W Burridge 11,  Francisco Martin 12,  Luis Javier Martínez-González 13,  Cristina Lucía Dávila-Fajardo 14
Affiliations

Affiliations

  • 1 GENYO: Center for Genomics and Oncological Research: Pfizer-University of Granada-Junta de Andalucía, Granada, Spain. Electronic address: [email protected].
  • 2 GENYO: Center for Genomics and Oncological Research: Pfizer-University of Granada-Junta de Andalucía, Granada, Spain. Electronic address: [email protected].
  • 3 GENYO: Center for Genomics and Oncological Research: Pfizer-University of Granada-Junta de Andalucía, Granada, Spain. Electronic address: [email protected].
  • 4 Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, Granada, Spain. Electronic address: [email protected].
  • 5 Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address: [email protected].
  • 6 Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address: [email protected].
  • 7 GENYO: Center for Genomics and Oncological Research: Pfizer-University of Granada-Junta de Andalucía, Granada, Spain; Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, Granada, Spain. Electronic address: [email protected].
  • 8 General Surgery and Digestive System Service, Hospital Universitario San Cecilio, Granada, Spain. Electronic address: [email protected].
  • 9 General Surgery and Digestive System Service, Hospital Universitario San Cecilio, Granada, Spain. Electronic address: [email protected].
  • 10 GENYO: Center for Genomics and Oncological Research: Pfizer-University of Granada-Junta de Andalucía, Granada, Spain; Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, Granada, Spain; IBS, Biosanitary Research Institute (ibs. GRANADA), University of Granada, Granada, Spain. Electronic address: [email protected].
  • 11 Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address: [email protected].
  • 12 GENYO: Center for Genomics and Oncological Research: Pfizer-University of Granada-Junta de Andalucía, Granada, Spain; Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, Granada, Spain; IBS, Biosanitary Research Institute (ibs. GRANADA), University of Granada, Granada, Spain. Electronic address: [email protected].
  • 13 GENYO: Center for Genomics and Oncological Research: Pfizer-University of Granada-Junta de Andalucía, Granada, Spain; Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, Granada, Spain; IBS, Biosanitary Research Institute (ibs. GRANADA), University of Granada, Granada, Spain. Electronic address: [email protected].
  • 14 GENYO: Center for Genomics and Oncological Research: Pfizer-University of Granada-Junta de Andalucía, Granada, Spain; Pharmacy Department, Hospital Universitario Virgen de las Nieves - Instituto de Investigación Biosanitaria (ibs.Granada), Granada, Spain. Electronic address: [email protected].
PMID: 41423083 DOI: 10.1016/j.ejphar.2025.178484
Abstract

Aims: Treatment of HER2 positive (HER2+) breast Cancer has significantly improved since the development of trastuzumab. However, approximately 30 % of patients develop trastuzumab-induced cardiotoxicity (TIC) manifested as a decrease in left ventricular ejection fraction (LVEF), with nearly 5 % of cases progressing to congestive heart failure. While TIC is generally reversible upon treatment discontinuation, the underlying mechanisms of this adverse reaction remain incompletely understood. Emerging evidence suggests that genetic factors may contribute to individual susceptibility. The variant rs1136201 in the ERBB2 gene, also known as HER2 Ile655Val or I655V, has been studied for its association with TIC, yet its role remains controversial. This study investigates the implication of the rs1136201 variant in cardiotoxicity in in vitro models of human cardiomyocytes exposed to trastuzumab.

Methods and results: We generated AC16 ventricular cardiomyocyte cell models representing the three genotypes of the rs1136201 variant and performed transcriptomic analysis following trastuzumab exposure. Furthermore, we established a second model consisting of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients carrying the rs1136201 variant and controls and evaluated the impact of this variant on mitochondrial function and contractility after trastuzumab treatment. Transcriptomic analysis revealed alteration of the electron transport chain, ATP synthesis, cellular respiration, and ribosome biogenesis in cells carrying the rs1136201 variant after trastuzumab exposure. hiPSC-CMs showed a reduction in upstroke (p = 0.0107) and downstroke velocities (p = 0.0117) compared to controls.

Conclusion: Our preliminary findings support the potential role of rs1136201 in TIC and underscore the need for further studies.

Keywords

Cardiomyocytes; Cardiotoxicity; Contractility; HER2 Ile655Val; Mitochondria; Trastuzumab.

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