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

Arun Sharma, Paul W. Burridge, Wesley L. McKeithan, Ricardo Serrano, Praveen Shukla, Nazish Sayed, Jared M. Churko, Tomoya Kitani, Haodi Wu, Alexandra Holmström, Elena Matsa, Yuan Zhang, Anusha Kumar, Alice C. Fan, Juan C. Del Álamo, Sean M. Wu, Javid J. Moslehi, Mark Mercola, Joseph C. Wu

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbereaaf2584
JournalScience Translational Medicine
Volume9
Issue number377
DOIs
StatePublished - Feb 15 2017
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sharma, A., Burridge, P. W., McKeithan, W. L., Serrano, R., Shukla, P., Sayed, N., ... Wu, J. C. (2017). High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells. Science Translational Medicine, 9(377), [eaaf2584]. https://doi.org/10.1126/scitranslmed.aaf2584

High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells. / Sharma, Arun; Burridge, Paul W.; McKeithan, Wesley L.; Serrano, Ricardo; Shukla, Praveen; Sayed, Nazish; Churko, Jared M.; Kitani, Tomoya; Wu, Haodi; Holmström, Alexandra; Matsa, Elena; Zhang, Yuan; Kumar, Anusha; Fan, Alice C.; Del Álamo, Juan C.; Wu, Sean M.; Moslehi, Javid J.; Mercola, Mark; Wu, Joseph C.

In: Science Translational Medicine, Vol. 9, No. 377, eaaf2584, 15.02.2017.

Research output: Contribution to journalArticle

Sharma, A, Burridge, PW, McKeithan, WL, Serrano, R, Shukla, P, Sayed, N, Churko, JM, Kitani, T, Wu, H, Holmström, A, Matsa, E, Zhang, Y, Kumar, A, Fan, AC, Del Álamo, JC, Wu, SM, Moslehi, JJ, Mercola, M & Wu, JC 2017, 'High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells', Science Translational Medicine, vol. 9, no. 377, eaaf2584. https://doi.org/10.1126/scitranslmed.aaf2584
Sharma, Arun ; Burridge, Paul W. ; McKeithan, Wesley L. ; Serrano, Ricardo ; Shukla, Praveen ; Sayed, Nazish ; Churko, Jared M. ; Kitani, Tomoya ; Wu, Haodi ; Holmström, Alexandra ; Matsa, Elena ; Zhang, Yuan ; Kumar, Anusha ; Fan, Alice C. ; Del Álamo, Juan C. ; Wu, Sean M. ; Moslehi, Javid J. ; Mercola, Mark ; Wu, Joseph C. / High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells. In: Science Translational Medicine. 2017 ; Vol. 9, No. 377.
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AU - Shukla, Praveen

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AU - Churko, Jared M.

AU - Kitani, Tomoya

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AU - Matsa, Elena

AU - Zhang, Yuan

AU - Kumar, Anusha

AU - Fan, Alice C.

AU - Del Álamo, Juan C.

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