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Sci Transl Med. 2017 Feb 15;9(377). pii: eaaf2584. doi: 10.1126/scitranslmed.aaf2584.

High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells.

Sharma A1,2,3, Burridge PW1,2,4, McKeithan WL1,5,6, Serrano R7, Shukla P1,2,3, Sayed N1,2,3, Churko JM1,2,3, Kitani T1,2,3, Wu H1,2,3, Holmström A1,2,3, Matsa E1,2,3, Zhang Y1,2,3, Kumar A1,2,3, Fan AC8, Del Álamo JC7, Wu SM1,2,3, Moslehi JJ9, Mercola M1,3,5, Wu JC10,2,3.

Author information

1
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Department of Pharmacology and Center for Pharmacogenomics, Northwestern University School of Medicine, Chicago, IL 60611, USA.
5
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
6
Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
7
Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA 92092, USA.
8
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
9
Division of Cardiovascular Medicine, Cardio-Oncology Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
10
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. joewu@stanford.edu.

Abstract

Tyrosine kinase inhibitors (TKIs), despite their efficacy as anticancer therapeutics, are associated with cardiovascular side effects ranging from induced arrhythmias to heart failure. We used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), generated from 11 healthy individuals and 2 patients receiving cancer treatment, to screen U.S. Food and Drug Administration-approved TKIs for cardiotoxicities by measuring alterations in cardiomyocyte viability, contractility, electrophysiology, calcium handling, and signaling. With these data, we generated a "cardiac safety index" to reflect the cardiotoxicities of existing TKIs. TKIs with low cardiac safety indices exhibit cardiotoxicity in patients. We also derived endothelial cells (hiPSC-ECs) and cardiac fibroblasts (hiPSC-CFs) to examine cell type-specific cardiotoxicities. Using high-throughput screening, we determined that vascular endothelial growth factor receptor 2 (VEGFR2)/platelet-derived growth factor receptor (PDGFR)-inhibiting TKIs caused cardiotoxicity in hiPSC-CMs, hiPSC-ECs, and hiPSC-CFs. With phosphoprotein analysis, we determined that VEGFR2/PDGFR-inhibiting TKIs led to a compensatory increase in cardioprotective insulin and insulin-like growth factor (IGF) signaling in hiPSC-CMs. Up-regulating cardioprotective signaling with exogenous insulin or IGF1 improved hiPSC-CM viability during cotreatment with cardiotoxic VEGFR2/PDGFR-inhibiting TKIs. Thus, hiPSC-CMs can be used to screen for cardiovascular toxicities associated with anticancer TKIs, and the results correlate with clinical phenotypes. This approach provides unexpected insights, as illustrated by our finding that toxicity can be alleviated via cardioprotective insulin/IGF signaling.

PMID:
28202772
PMCID:
PMC5409837
DOI:
10.1126/scitranslmed.aaf2584
[Indexed for MEDLINE]
Free PMC Article

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