Transcriptomic profiling of drug-treated human induced pluripotent stem cells (iPSCs) [DGE-GEO-Depot]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE217423 | GEO | 2022/11/14
REPOSITORIES: GEO
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Project description:Kinase inhibitors (KIs) are a promising alternative to traditional chemotherapeutics in the treatment of multiple cancer types. Unfortunately, some kinase inhibitors induce cardiotoxicity as a severe side effect. To identify gene expression signatures that might be indicative of kinase inhibitor-induced cardiotoxicity, we generated six cardiomyocyte cell lines from induced pluripotent stem cells that we obtained from six healthy volunteers. Treatment of these cell lines with 54 FDA-approved drugs, i.e. 23 kinase inhibitors, 4 monoclonal antibodies, 4 anthracyclines, 7 cardiac acting and 16 non-cardiac acting drugs, allowed generation of 266 lists of differentially expressed genes. We subjected those lists to unsupervised and supervised algorithms to identify differentially expressed pathway activities associated with cardiotoxic responses.
2022-11-14 | GSE217421 | GEO
Project description:Kinase inhibitors (KIs) represent an important class of anti-cancer drugs. Although cardiotoxicity is a serious adverse event associated with several KIs, the reasons remain poorly understood and its prediction remains challenging. Here, we perform transcriptomic profiling of human heart-derived primary cardiomyocyte cell lines treated with a panel of 26 FDA-approved KIs and classify their effects on subcellular pathways and processes. Individual cardiotoxicity patient reports for these KIs, obtained from the FDA Adverse Event Reporting System, are used to compute relative risk scores. These are then combined with cell line-derived transcriptomic datasets through elastic net regression analysis to identify a gene signature that can predict risk of cardiotoxicity. We also identify relationships between cardiotoxicity risk and structural/binding profiles of individual KIs. We conclude that acute transcriptomic changes in cell-based assays combined with drug substructures are predictive of KI-induced cardiotoxicity risk, and that they can be informative for future drug discovery.
2020-05-13 | GSE146096 | GEO
Project description:Kinase inhibitors (KIs) represent an important class of anti-cancer drugs. Although cardiotoxicity is a serious adverse event associated with several KIs, the reasons remain poorly understood and its prediction remains challenging. Here, we perform transcriptomic profiling of human heart-derived primary cardiomyocyte cell lines treated with a panel of 26 FDA-approved KIs and classify their effects on subcellular pathways and processes. Individual cardiotoxicity patient reports for these KIs, obtained from the FDA Adverse Event Reporting System, are used to compute relative risk scores. These are then combined with cell line-derived transcriptomic datasets through elastic net regression analysis to identify a gene signature that can predict risk of cardiotoxicity. We also identify relationships between cardiotoxicity risk and structural/binding profiles of individual KIs. We conclude that acute transcriptomic changes in cell-based assays combined with drug substructures are predictive of KI-induced cardiotoxicity risk, and that they can be informative for future drug discovery.
2020-05-13 | GSE146095 | GEO
Project description:A major class of chemotherapeutics targets topoisomerase II for DNA double-strand breaks and cancer cell elimination. We compare four members of this class?the anthracyclines doxorubicin, daunorubicin and aclarubicin that does not induce DNA breaks?and a different compound, etoposide. We define a novel activity for anthracyclines: histone eviction from open chromosomal areas. Since histone variant H2AX is also evicted, DNA damage response is attenuated when compared to etoposide. Histone eviction also affects the epigenetic code and deregulates the transcriptome in cancer cells and organs such as the heart. Histone eviction by anthracyclines can drive apoptosis of topoisomerase-negative acute myeloid leukemia blasts in patients. Doxo- and daunorubicin combine the activities of two anti-cancer drugs: etoposide for DNA damage and aclarubicin for histone eviction. We define a novel mechanism of action of anti-cancer drugs doxo- and daunorubicin on chromatin biology with profound consequences on DNA damage responses, epigenetics, transcription, side effects and anti-cancer activities. Comparison of histone occupancy of cells or tissues treated with topoisomerase II inhibitors to un-treated ones by FAIRE-seq.
2013-06-04 | E-GEOD-33632 | biostudies-arrayexpress
Project description:Cardiotoxicity remains a major cause of drug withdrawal, partially due to lacking predictability of animal models. Additionally, risk of cardiotoxicity following treatment of cancer patients is treatment limiting. It is unclear which patients will develop heart failure following therapy. Human pluripotent stem cell (hPSC)-derived cardiomyocytes present an unlimited cell source and may offer individualized solutions to this problem. We developed a platform to predict molecular and functional aspects of cardiotoxicity. Our platform can discriminate between the different cardiotoxic mechanisms of existing and novel anthracyclines Doxorubicin (DOXO), Aclarubicin (ACLA) and Amrubicin (AMR). DOXO and ACLA unlike AMR substantially affected the transcriptome, mitochondrial membrane integrity, contractile force and transcription factor availability. Cardiomyocytes recovered fully within two or three weeks, corresponding to the intermittent clinical treatment regimen. Our system permits the study of hPSC-cardiomyocyte recovery and the effects of accumulated dose after multiple dosing, allowing individualized cardiotoxicity evaluation, which effects millions of cancer patients treated with anthracyclines annually.
2023-10-01 | GSE232331 | GEO
Project description:Long-term side effects of doxorubicin include cardiotoxicity. Because studying transcriptional network alterations in human heart at early stages of cardiac dysfunction development is not feasible, in the present study, we used circulating microRNAs (miRNAs) to obtain insight into cellular processes in acute lymphoblastic leukemia (ALL) survivors with a history of doxorubicin treatment. We showed that altered miRNA profiles in plasma and circulating extracellular vesicles (EVs) and particularly the distribution of miRNAs between the two compartments in ALL survivors are linked to cellular transcriptomic processes controlled by transcription factors involved in epigenetic regulation, oxidative stress response, senescence, fibrosis, or epithelial-mesenchymal transition (EMT)—a phenomenon involved in organ injury, repair, and remodeling. These alterations could also be linked to cardiac complications and interindividual variability in cardiomyocyte response to doxorubicin. Thus, circulating miRNAs can indicate the possible molecular mechanisms of cardiotoxicity in patients previously exposed to anthracyclines even when there are no apparent clinical signs of heart dysfunction.
2023-01-05 | GSE145176 | GEO
Project description:The clinical application of anthracyclines such as doxorubicin (DOX) is limited due to their cardiotoxicity. N6-methyladenosine (m6A) plays an essential role in numerous biological processes. However, the roles of m6A and m6A demethylase ALKBH5 in DOX-induced cardiotoxicity (DIC) remain unclear. In this research, DIC models were constructed using Alkbh5-knockout (KO), Alkbh5-knockin (KI), and Alkbh5-myocardial-specific knockout (ALKBH5flox/flox, αMyHC-Cre) mice. Cardiac function and DOX-mediated signal transduction were investigated. As a result, both Alkbh5 whole-body KO and myocardial-specific KO mice had increased mortality, decreased cardiac function, and aggravated DIC injury with severe myocardial mitochondrial damage. Conversely, ALKBH5 overexpression alleviated DOX-mediated mitochondrial injury, increased survival, and improved myocardial function. Mechanistically, ALKBH5 regulated the expression of Rasal3 in an m6A-dependent manner through posttranscriptional mRNA regulation and reduced Rasal3 mRNA stability, thus activating RAS3, inhibiting apoptosis through the RAS/RAF/ERK signaling pathway, and alleviating DIC injury. These findings indicate the potential therapeutic effect of ALKBH5 on DIC.
2023-03-08 | GSE224215 | GEO
Project description:Tyrosine kinase inhibitors (TKIs), as a class of small-molecule drugs that exert anti-tumor effects by inhibiting tyrosine kinase-catalyzed phosphorylation, have been used in the treatment of various cancers. Sorafenib, as a multi-targeted TKI drug, is the first-line treatment for advanced renal cell carcinoma and unresectable hepatocellular carcinoma. However, sorafenib has repeatedly been reported to cause cardiac events in patients without a history of heart diseases during clinical use, indicating that it has cardiotoxicity. Alternative splicing of cardiac contraction-related genes happens during heart development and cardiac diseases, and is critical for heart function. However, whether alternative splicing plays a role in drug-induced cardiotoxicity remains unexplored. RBM20 is an important cardiac-specific splicing factor, mutations of which cause dilated cardiomyopathy or other cardiac dysfunctions. Rbm20 also mediates alternative splicing of genes essential for heart contraction, which is often negatively affected in drug-induced cardiotoxicity. Existing studies do not fully explain the mechanism of sorafenib cardiotoxicity, and none of the relationship between cardiotoxicity of sorafenib and alternative splicing mediated by tissue-specific splicing factors, such as Rbm20, have been reported. In order to explore whether cardiac-specific alternative splicing plays a role in sorafenib-induced cardiotoxicity, we establish both cell and animal models of cardiotoxicity, and obtain the following results: (1) By constructing a rat animal model administered with sorafenib, we find that sorafenib causes abnormal cardiac function in rats, and the genes that undergo alternative splicing in rat hearts are related to cytoskeleton of actin; (2) Alternatively spliced genes induced by sorafenib in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are enriched in sarcomere, actin filament, calcium transient regulation, mitochondria, all of which are critical for cardiac contraction. These genes are associated with dilated cardiomyopathy, hypertrophic cardiomyopathy and other cardiomyopathy; (3) Sorafenib induces a decrease in the expression of cardiac-specific splicing factor RBM20; (3) Many genes whose splicing are altered by sorafenib overlap with Rbm20 targets, indicating that sorafenib may affect alternative splicing through Rbm20; (4) Sorafenib induces pathogenic alternative splicing of FHOD3, which is a RBM20 target gene and participates in myocardial sarcomere formation. Sorafenib also affects alternative splicing of SLC25A3, which encodes a phosphate transporter on the mitochondrial inner membrane and regulates ATP synthesis; (5) Enhancing the expression of RBM20 rescues the cardiotoxicity of sorafenib by reducing apoptosis and increasing ATP levels, which is mediated by reversing the alternative splicing of FHOD3 and SLC25A3 induced by sorafenib. This paper uncovers that sorafenib reduces the expression of RBM20 to cause pathogenic alternative splicing of genes related to myocardial sarcomere and energy mechanism, resulting in abnormal myocardial function. Increasing the expression of RBM20 reverses the alternative splicing of FHOD3 and SLC25A3 associated with cardiac sarcomeres and mitochondria respectively, rescuing the cardiotoxicity of sorafenib.
2023-12-07 | GSE222642 | GEO
Project description:Drug-induced cardiotoxicity is a widespread clinical issue affecting numerous drug classes and remains difficult to treat. One such drug class is Tyrosine Kinase Inhibitors (TKIs), which cause varying degrees of contraction-related cardiotoxicity usually after weeks of exposure. Understanding molecular mechanisms underlying both acute and chronic toxicity of TKIs could help identify new treatment opportunities. Here, we presented transcriptome responses to four TKIs (Sunitinib, Sorafenib, Lapatinib and Erlotinib) across 3 doses and 4 time points in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Gene expression evolved continually under drug treatment and revealed changes in several biological networks that were associated with cardiac metabolism and contraction. These changes were confirmed by proteomics and resulted in metabolic and structural remodeling of hiPSC-CMs. One of the metabolic remodeling was the increased aerobic glycolysis induced by Sorafenib, which is an adaptive response in preserving cell survival under Sorafenib treatment. Drug adaptation in cardiac cells may represent new targets for managing chronic forms of TKI-induced cardiotoxicity.
2019-05-16 | PXD012043 | Pride
Project description:TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.
2024-02-01 | GSE243674 | GEO