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Tyrosine Kinase Inhibitor Cardiotoxicity

ABSTRACT: Tyrosine Kinase Inhibitor Cardiotoxicity

PROVIDER: PRJNA352077 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR4432910_1.fastq.gz	Fastqsanger.gz
	SRR4432910_2.fastq.gz	Fastqsanger.gz
	SRR4432901_1.fastq.gz	Fastqsanger.gz
	SRR4432901_2.fastq.gz	Fastqsanger.gz
	SRR4432902_1.fastq.gz	Fastqsanger.gz

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High-Throughput Screening of Human Induced Pluripotent Stem Cell Cardiomyocytes Predicts Tyrosine Kinase Inhibitor Cardiotoxicity

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Project description:Tyrosine kinase inhibitors (TKIs) are anti-cancer therapeutics used in long-term treatment. However, many of them cause cardiotoxicity with limited cure. We aim to define molecular mechanisms of cardiotoxicity that can be targeted for oncocardiology treatment. Eight TKIs with different levels of cardiotoxicity were selected and transcriptome responses of human cardiomyocytes to them at varying doses and times were profiled using a high throughput RNAseq technique. Transcriptome changes are classified into 7 clusters with mainly single-drug clusters. Drug-specific effects on the transcriptome dominate over dose-, time- or toxicity-dependent effects. Two clusters with three TKIs (afatinib, ponatinib and sorafenib) have the top enriched pathway as the endoplasmic reticulum stress. These TKIs cause an increase in reactive oxygen species, lipid peroxidation, or calcium, and induce biased endoplasmic reticulum stress on the PERK and the IRE1α pathway. Inhibiting either PERK or IRE1α blocks expression of cardiomyocyte injury and pro-inflammatory markers. Our data contain rich information about stress responses of human cardiomyocytes to specific TKIs, representing potential molecular mechanisms of cardiotoxicity. ER stress-induced inflammation is a promising therapeutic target to mitigate ponatinib- and sorafenib-induced cardiotoxicity

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High-Throughput Screening of Tyrosine Kinase Inhibitor Cardiotoxicity using Human Induced Pluripotent Stem Cells

Project description:Tyrosine kinase inhibitors (TKIs), despite efficacy as anti-cancer therapies, are associated with cardiovascular side effects ranging from induced arrhythmias to heart failure. We have utilized patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), generated from 11 healthy individuals and 2 patients receiving cancer treatment, to screen FDA-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 assess cardiotoxicities of existing TKIs. Many TKIs with a low cardiac safety index 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 VEGFR2/PDGFR-inhibiting TKIs caused cardiotoxicity in hiPSC-CMs, hiPSC-ECs, and hiPSC-CFs. Using 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. Activating cardioprotective signaling with exogenous insulin or IGF1 improved hiPSC-CM viability during co-treatment with cardiotoxic VEGFR2/PDGFR-inhibiting TKIs. Thus, hiPSC-CMs can be used to screen for cardiovascular toxicities associated with anti-cancer TKIs, correlating 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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Project description:To define molecular markers of tyrosine kinase inhibitor-induced cardiotoxicity, we measured transcriptome changes in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with one of four tyrosine kinase inhibitors (Erlotinib, Lapatinib, Sorafenib, or Sunitinib) displaying a range of mild to severe cardiotoxicity or a vehicle-only control (DMSO). Gene expression changes were assessed at the cell population level using total RNA-seq, which measured levels of both mRNAs and non-coding RNAs. hiPSC-CMs used in this study were the Cor.4U cells purchased from Ncardia.

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Highly efficient and multiplexed transcriptome profiling of cardiotoxicity induced by tyrosine kinase inhibitors

Project description:Highly efficient and multiplexed transcriptome profiling of cardiotoxicity induced by tyrosine kinase inhibitors

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Tyrosine Kinase Inhibitor Cardiotoxicity

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-11-02 | GSE89411 | GEO

Transcriptomic profiling of human cardiac cells predicts protein kinase inhibitor-associated cardiotoxicity

Project description:Transcriptomic profiling of human cardiac cells predicts protein kinase inhibitor-associated cardiotoxicity

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Transcriptomic profiling of human cardiac cells predicts protein kinase inhibitor-associated cardiotoxicity [DGE]

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Project description:Interventions: Group 1: Patients with Gastrointestinal Stromal Tumors undergoing tyrosine kinase inhibitor treatment will be assessed regarding progression-free survival and overall survival within 2 years using the standard response criteria, in particular Response Evaluation Criteria In Solid Tumors, the WHO criteria for response, the tumor lesion volume as well as tumor density (according to Choi). Group 2: Patients with Gastrointestinal Stromal Tumors undergoing tyrosine kinase inhibitor treatment will be assessed regarding progression-free survival and overall survival within 2 years using the response criteria, in particular tumor lesion iodine uptake. Primary outcome(s): Progression-free survival within 2 years. Study Design: Allocation: Non-randomized controlled study; Masking: Open (masking not used); Control: active; Assignment: parallel; Study design purpose: treatment

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