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 language | English (US) |
|---|---|
| Article number | eaaf2584 |
| Journal | Science Translational Medicine |
| Volume | 9 |
| Issue number | 377 |
| DOIs | |
| State | Published - Feb 15 2017 |
| Externally published | Yes |
ASJC Scopus subject areas
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells
AU - Sharma, Arun
AU - Burridge, Paul W.
AU - McKeithan, Wesley L.
AU - Serrano, Ricardo
AU - Shukla, Praveen
AU - Sayed, Nazish
AU - Churko, Jared M.
AU - Kitani, Tomoya
AU - Wu, Haodi
AU - Holmström, Alexandra
AU - Matsa, Elena
AU - Zhang, Yuan
AU - Kumar, Anusha
AU - Fan, Alice C.
AU - Del Álamo, Juan C.
AU - Wu, Sean M.
AU - Moslehi, Javid J.
AU - Mercola, Mark
AU - Wu, Joseph C.
PY - 2017/2/15
Y1 - 2017/2/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85013498342&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85013498342&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aaf2584
DO - 10.1126/scitranslmed.aaf2584
M3 - Article
C2 - 28202772
AN - SCOPUS:85013498342
VL - 9
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 377
M1 - eaaf2584
ER -