Modeling trastuzumab-related cardiotoxicity in vitro using human stem cell-derived cardiomyocytes

Yosuke K. Kurokawa, Michael R. Shang, Rose T. Yin, Steven George

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Trastuzumab (Herceptin®), a monoclonal antibody against the ErbB2 (HER2) receptor, has significantly improved clinical outcomes for HER2+ breast cancer patients. However, the drug also has known cardiotoxic side effects through mechanisms that are not fully understood. Here we utilized human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) to model trastuzumab-related cardiotoxicity in vitro. We demonstrate that cardiotoxic effects of ErbB2 inhibition by trastuzumab can be recapitulated only when the cardioprotective effects of ErbB2/4 signaling is observed. We observed no cardioprotective effects of ErbB2/4 signaling without cellular stress (doxorubicin exposure in this study). In addition to neuregulin-1 (NRG-1), we show that heparin-binding epidermal growth factor-like growth factor (HB-EGF) also provides cardioprotective effects for iPS-CMs. Finally, we demonstrate a simple, high-throughput co-culture platform utilizing iPS-CMs and endothelial cells that is capable of detecting trastuzumab-related cardiotoxicity. We conclude that iPS-CMs can recapitulate trastuzumab-related cardiotoxicity, and may be used to elucidate additional modes of toxicity of trastuzumab and related compounds.

Original languageEnglish (US)
Pages (from-to)74-80
Number of pages7
JournalToxicology Letters
Volume285
DOIs
StatePublished - Mar 15 2018

Keywords

  • Cardiotoxicity
  • ErbB2
  • Neuregulin
  • Stem cell-derived cardiomyocytes

ASJC Scopus subject areas

  • Toxicology

Fingerprint Dive into the research topics of 'Modeling trastuzumab-related cardiotoxicity in vitro using human stem cell-derived cardiomyocytes'. Together they form a unique fingerprint.

  • Cite this