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.
N1 - Funding Information:
We acknowledge support from the American Heart Association Predoctoral Fellowship (13PRE15770000) and NSF Graduate Research Fellowship (DGE-114747) (A.S.); NIH (K99/R00 HL121177) and American Heart Association Beginning Grant-in-Aid (14BGIA20480329) (P.W.B.); NIH Director's Pioneer Award, American Heart Association Grant-in-Aid, and Endowed Faculty Scholar Award of the Lucile Packard Foundation for Children and Child Health Research Institute at Stanford (S.M.W.); and Burroughs Wellcome Foundation Innovation in Regulatory Science, American Heart Association Established Investigator Award, and NIH (R01 HL132875, R01 HL130020, R01 HL128170, R01 HL123968, and R24 HL117756) (J.C.W.).
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.
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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 -