# Characterization and Genetics of KI toxicity in iPSC-derived cardiomyocytes

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $744,112

## Abstract

Abstract
The development of kinase inhibitors (KIs) has revolutionized the treatment of a broad spectrum
of cancer types. However drug-related adverse effects often counter the benefits of anti-cancer
drugs. With the widespread use of KIs, it has become apparent that a subset of patients
develops cardiac dysfunction and heart failure. Currently our knowledge of the underlying
pathophysiology and risk factors is limited. Experiments focusing on understanding the
molecular and genetic mechanisms underlying cardiotoxicity will be critical to improve and guide
further drug development. The recent development of human induced pluripotent stem cells
(hiPSCs) and the ability to differentiate hiPSCs into CMs (hiPSC-CMs) offer unprecedented
opportunities for disease modeling and cardiotoxicity testing. Human iPSC-CMs exhibit
properties highly similar to their primary counterparts, thus providing a relevant `patient in a dish'
model. The overarching goal of this proposal is to identify and understand the molecular and
genetic mechanisms underlying KI-induced cardiotoxicity by using hiPSC-CMs.
The proposal builds on extensive infrastructure funded through various NHLBI grants. We have
generated 250 hiPSCs lines and differentiated these lines into CMs from participants in the
NHLBI HyperGEN cohort. We propose to use these hiPSC-CMs to identify underlying pathways
and genetic markers, which contribute to the variability in the response to KIs. Using expression
analysis, we will describe the distinct molecular responses associated with exposing hiPSC-
CMs to KIs. We will perform standard phenotypic analyses, expression analysis and functional
assays for cardiotoxicity. Subsequently we will perform pathway expression analysis to identify
novel functional networks associated with KI cardiotoxicity. In addition, we will be utilizing
previously obtained GWAS and whole exome sequencing data to perform expression
quantitative trait locus analysis to determine variants associated with KI-induced cardiotoxicity.
Our proposal applies a precision and systems medicine approach to the study of cardiotoxicity.
Furthermore the proposed approach can provide important insights for the future development
of novel KIs with a reduced cardiotoxic risk profile.

## Key facts

- **NIH application ID:** 9917814
- **Project number:** 5R01HL140493-03
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** ULRICH BROECKEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $744,112
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917814

## Citation

> US National Institutes of Health, RePORTER application 9917814, Characterization and Genetics of KI toxicity in iPSC-derived cardiomyocytes (5R01HL140493-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9917814. Licensed CC0.

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