# Elucidating Genetic Susceptibility of Covalent Kinase Inhibitors with iPSC "Cell Village"

> **NIH NIH P01** · STANFORD UNIVERSITY · 2024 · $584,552

## Abstract

PROJECT SUMMARY
Cancer and cardiovascular diseases are the two leading causes of death in the US and worldwide. Despite the
development of second-generation targeted cancer therapies, including covalent tyrosine kinase inhibitors
(TKIs), these chemotherapy agents frequently cause significant cardiovascular toxicities (CTX). Understanding
the mechanism of CTX susceptibility and developing mitigation strategies are major current challenges in this
field. In Project 2, our team will elucidate the genetic susceptibility of cancer patients to the CTX after treatment
with ibrutinib, a covalent Bruton kinase inhibitor. In Aim 1, we will harness multiomics and new multiplexing
methodology known as “cell village” to perform population level studies in vitro. In collaboration with Project 1
and Core B, we will recruit ibrutinib-treated patients who developed CTX (“ibrutinib-CTX”) and ibrutinib-treated
patients who did not develop CTX (“ibrutinib-nonCTX”) to generate induced pluripotent stem cells (iPSCs). The
multiplexing capability of the patient-derived iPSCs will be utilized to form “cell village” pools that can be
differentiated into cardiomyocytes (iPSC-CMs). The effect of ibrutinib will be monitored on the transcriptome and
epigenome level through single-cell multiomics sequencing technology. In Aim 2, these changes will be
examined using expression quantitative trait loci (eQTL) studies to detect variants causal for CTX development,
which will be further screened for mitigating pathways in collaboration with Project 3. In Aim 3, we will validate
the causality of the top 3 detected genetic variants via genome editing in iPSC lines. The edited lines will then
undergo comprehensive functional studies using 3D models of iPSC-derived cardiac organoids (iPSC-COs). In
summary, understanding the mechanism and genetic background of ibrutinib-induced cardiotoxicity will
contribute significantly to developing patient-specific strategies that can mitigate adverse effects of these drugs.
Once established, this versatile and high throughput genetic screening strategy can also be expanded to
encompass other covalent TKIs and cancer drugs.

## Key facts

- **NIH application ID:** 10935740
- **Project number:** 2P01HL141084-06
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Joseph C. Wu
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $584,552
- **Award type:** 2
- **Project period:** 2019-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935740

## Citation

> US National Institutes of Health, RePORTER application 10935740, Elucidating Genetic Susceptibility of Covalent Kinase Inhibitors with iPSC "Cell Village" (2P01HL141084-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10935740. Licensed CC0.

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