The antineoplastic drug, trastuzumab, dysregulates metabolism in iPSC-derived cardiomyocytes

Brian M. Necela, Bianca C. Axenfeld, Daniel J. Serie, Jennifer M. Kachergus, Edith A. Perez, E. Aubrey Thompson, Nadine Norton

Research output: Contribution to journalArticle

Abstract

Background: The targeted ERBB2 therapy, trastuzumab, has had a tremendous impact on management of patients with HER2+ breast cancer, leading to development and increased use of further HER2 targeted therapies. The major clinical side effect is cardiotoxicity but the mechanism is largely unknown. On the basis that gene expression is known to be altered in multiple models of heart failure, we examined differential gene expression of iPSC-derived cardiomyocytes treated at day 11 with the ERBB2 targeted monoclonal antibody, trastuzumab for 48 h and the small molecule tyrosine kinase inhibitor of EGFR and ERBB2. Results: Transcriptome sequencing was performed on four replicates from each group (48 h untreated, 48 h trastuzumab and 48 h lapatinib) and differential gene expression analyses were performed on each treatment group relative to untreated cardiomyocytes. 517 and 1358 genes were differentially expressed, p < 0.05, respectively in cardiomyocytes treated with trastuzumab and lapatinib. Gene ontology analyses revealed in cardiomyocytes treated with trastuzumab, significant down-regulation of genes involved in small molecule metabolism (p = 3.22 � 10-9) and cholesterol (p = 0.01) and sterol (p = 0.03) processing. We next measured glucose uptake and lactate production in iPSC-derived cardiomyocytes 13 days post-plating, treated with trastuzumab up to 96 h. We observed significantly decreased glucose uptake from the media of iPSC-derived cardiomyocytes treated with trastuzumab as early as 24 h (p = 0.001) and consistently up to 96 h (p = 0.03). Conclusions: Our study suggests dysregulation of cardiac gene expression and metabolism as key elements of ERBB2 signaling that could potentially be early biomarkers of cardiotoxicity.

Original languageEnglish (US)
Article number5
JournalClinical and Translational Medicine
Volume6
Issue number1
DOIs
StatePublished - Jan 18 2017

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Cardiac Myocytes
Antineoplastic Agents
Gene Expression
Glucose
Gene Ontology
Sterols
Trastuzumab
Transcriptome
Protein-Tyrosine Kinases
Genes
Lactic Acid
Therapeutics
Down-Regulation
Heart Failure
Biomarkers
Cholesterol
Monoclonal Antibodies
Breast Neoplasms

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Molecular Medicine

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The antineoplastic drug, trastuzumab, dysregulates metabolism in iPSC-derived cardiomyocytes. / Necela, Brian M.; Axenfeld, Bianca C.; Serie, Daniel J.; Kachergus, Jennifer M.; Perez, Edith A.; Thompson, E. Aubrey; Norton, Nadine.

In: Clinical and Translational Medicine, Vol. 6, No. 1, 5, 18.01.2017.

Research output: Contribution to journalArticle

Necela, Brian M. ; Axenfeld, Bianca C. ; Serie, Daniel J. ; Kachergus, Jennifer M. ; Perez, Edith A. ; Thompson, E. Aubrey ; Norton, Nadine. / The antineoplastic drug, trastuzumab, dysregulates metabolism in iPSC-derived cardiomyocytes. In: Clinical and Translational Medicine. 2017 ; Vol. 6, No. 1.
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