Adaptation of human iPSC-derived cardiomyocytes to tyrosine kinase inhibitors reduces acute cardiotoxicity via metabolic reprogramming

Wang, Huan; Sheehan, Richard G.; Palmer, Adam C.; Everley, Robert A.; Boswell, Sarah A.; Ron-Harel, Noga; Ringel, Alison E.; Holton, Kristina M.; Jacobson, Connor A.; Erickson, Alison R.; Maliszewski, Laura; Haigis, Marcia C.; Sorger, Peter K.

doi:10.1101/365841

Cited by 7 publications

(7 citation statements)

References 51 publications

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“…Cardiotoxicity is typically defined as toxicity that adversely affects the heart and may eventually lead to cardiomyopathy [2]. A variety of anticancer drugs, such as immune checkpoint inhibitors (ICIs), TKIs [3], proteasome inhibitors [4], and microtubule inhibitors [5], have shown to exert harmful effects on the cardiovascular system through their own toxic effects or increasing the side effects of other drugs [6]. Moreover, some of them [7] could induce life-threatening cardiotoxicity such as ischemia, infarction, arrhythmia, and damage to cardiac valves, the conduction system, or the pericardium [8].…”

Section: Introductionmentioning

confidence: 99%

Analysis and Validation of Differentially Expressed Ferroptosis-Related Genes in Regorafenib-Induced Cardiotoxicity

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Although tyrosine kinase inhibitors (TKIs) constitute a type of anticancer drugs, the underlying mechanisms of TKI-associated cardiotoxicity remain largely unknown. Ferroptosis is a regulated cell death form that implicated in several tumors’ biological processes. Our objective was to probe into the differential expression of ferroptosis-related genes in regorafenib-induced cardiotoxicity through multiple bioinformatics analysis and validation. Methods and Materials. Four adult human cardiomyocyte cell lines treated with regorafenib were profiled using Gene Expression Omnibus (GEO) (GSE146096). Differentially expressed genes (DEGs) were identified using DESeq2 in R (V.3.6.3). Then, Gene Ontology (GO) Enrichment Analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) Enrichment Analysis, and Gene Set Enrichment Analysis (GSEA) were used to explore DEGs’ bioinformatics functions and enriched pathways. We intersected DEGs with 259 ferroptosis-related genes from the FerrDb database. Finally, the mRNA levels of differentially expressed ferroptosis-related genes (DEFRGs) were validated in regorafenib-cultured cardiomyocytes to anticipate the link between DEFRGs and cardiotoxicity. Results. 747,1127,773 and 969 DEGs were screened out in adult human cardiomyocyte lines A, B, D, and E, respectively. The mechanism by which REG promotes cardiotoxicity associated with ferroptosis may be regulated by PI3K-Akt, TGF-beta, and MAPK. GSEA demonstrated that REG can promote cardiotoxicity by suppressing genes and pathways encoding extracellular matrix and related proteins, oxidative phosphorylation, or ATF-2 transcription factor network. After overlapping DEGs with ferroptosis-related genes, we got seven DEFRGs and found that ATF3, MT1G, and PLIN2 were upregulated and DDIT4 was downregulated. The ROC curve demonstrated that these genes predict regorafenib-induced cardiotoxicity well. Conclusion. We identified four DEFRGs which may become potential predictors and participate in the regorafenib-induced cardiotoxicity. Our findings provide possibility that targeting these ferroptosis-related genes may be an alternative for clinical prevention and therapy of regorafenib-related cardiotoxicity.

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Section: Introductionmentioning

confidence: 99%

Analysis and Validation of Differentially Expressed Ferroptosis-Related Genes in Regorafenib-Induced Cardiotoxicity

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…In this regard, determining the optimal dose of this drug in patients with a-DCM will be the key to maximize the clinical benefits and reduce the side effects. Previous TKI toxicity studies using iPSC-CMs, iPSC-endothelial cells, and iPSC-cardiac fibroblasts have shown that TKIs in general are toxic at concentrations higher than 1 μM ( 69 , 70 ). On the basis of our findings, 1 μM crenolanib conferred cardiac function improvement without compromising cardiomyocyte survival (fig.…”

Section: Discussionmentioning

confidence: 99%

Activation of PDGFRA signaling contributes to filamin C–related arrhythmogenic cardiomyopathy

et al. 2022

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FLNC truncating mutations ( FLNCtv ) are prevalent causes of inherited dilated cardiomyopathy (DCM), with a high risk of developing arrhythmogenic cardiomyopathy. We investigated the molecular mechanisms of mutant FLNC in the pathogenesis of arrhythmogenic DCM (a-DCM) using patient-specific induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). We demonstrated that iPSC-CMs from two patients with different FLNCtv mutations displayed arrhythmias and impaired contraction. FLNC ablation induced a similar phenotype, suggesting that FLNCtv are loss-of-function mutations. Coimmunoprecipitation and proteomic analysis identified β-catenin (CTNNB1) as a downstream target. FLNC deficiency induced nuclear translocation of CTNNB1 and subsequently activated the platelet-derived growth factor receptor alpha (PDGFRA) pathway, which were also observed in human hearts with a-DCM and FLNCtv . Treatment with the PDGFRA inhibitor, crenolanib, improved contractile function of patient iPSC-CMs. Collectively, our findings suggest that PDGFRA signaling is implicated in the pathogenesis, and inhibition of this pathway is a potential therapeutic strategy in FLNC-related cardiomyopathies.

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“…The highest magnitude of cardiotoxicity observed was induced by the VEGFR2/PDGFR-inhibiting TKIs. In a related study, Wang et al [ 162 ] assessed iPSC-CMs response to four widely administered TKIs (sunitinib, sorafenib, lapatinib and erlotinib), using functional assays, microscopy, RNA sequencing and mass spectrometry. In general, the TKIs affected tyrosine kinase-mediated signal transduction and cardiac metabolism.…”

Section: The Use Of Ipsc-cms For Disease Modeling and Developing Nmentioning

confidence: 99%

Drug Development and the Use of Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Disease Modeling and Drug Toxicity Screening

Ovics

Regev

Baskin

et al. 2020

IJMS

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Over the years, numerous groups have employed human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) as a superb human-compatible model for investigating the function and dysfunction of cardiomyocytes, drug screening and toxicity, disease modeling and for the development of novel drugs for heart diseases. In this review, we discuss the broad use of iPSC-CMs for drug development and disease modeling, in two related themes. In the first theme—drug development, adverse drug reactions, mechanisms of cardiotoxicity and the need for efficient drug screening protocols—we discuss the critical need to screen old and new drugs, the process of drug development, marketing and Adverse Drug reactions (ADRs), drug-induced cardiotoxicity, safety screening during drug development, drug development and patient-specific effect and different mechanisms of ADRs. In the second theme—using iPSC-CMs for disease modeling and developing novel drugs for heart diseases—we discuss the rationale for using iPSC-CMs and modeling acquired and inherited heart diseases with iPSC-CMs.

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Adaptation of human iPSC-derived cardiomyocytes to tyrosine kinase inhibitors reduces acute cardiotoxicity via metabolic reprogramming

Cited by 7 publications

References 51 publications

Analysis and Validation of Differentially Expressed Ferroptosis-Related Genes in Regorafenib-Induced Cardiotoxicity

Analysis and Validation of Differentially Expressed Ferroptosis-Related Genes in Regorafenib-Induced Cardiotoxicity

Activation of PDGFRA signaling contributes to filamin C–related arrhythmogenic cardiomyopathy

Drug Development and the Use of Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Disease Modeling and Drug Toxicity Screening

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