# Mechanisms of Cardiotoxicity Associated with Covalent Kinase Inhibitors

> **NIH NIH P01** · STANFORD UNIVERSITY · 2024 · $627,300

## Abstract

PROJECT SUMMARY (Project 1)
In the past two decades, the recognition that aberrant activation of kinases plays a critical role in the
pathogenesis of cancers, has stimulated efforts to develop kinase inhibitors for therapy. However, kinase
inhibitors (KI) can lead to adverse cardiovascular effects, either due to the inhibition of the intended kinase target
(“on-target”) or another kinase (“off-target”). Existing needs in the field include understanding the paradigm of
“on-target” versus “off-target” and the need for generating a pre-clinical model to model drug toxicity in patients.
Project 1 of this PPG will focus on establishing pre-clinical models of covalent kinase inhibitor-associated
cardiotoxicity and attempt to understand the underlying mechanisms of toxicity. Specifically, ibrutinib (a first in-
class covalent KI) is associated with arrhythmia (especially atrial fibrillation), representing a unique and novel
toxicity. In Aim 1, we will utilize cell-based and novel genetic tools to examine that ibrutinib cardiotoxicity is
mediated via an “off-target” kinase, C-terminal Src Kinase (CSK). In Aim 2 we will use mouse models to show a
critical role for CSK in cardiotoxicity and test an additional hypothesis that ibrutinib treatment leads to cardiac
remodeling which further contributes to electrophysiologic effects. Aim 3 will use our clinical/pharmacovigilance
databases to corroborate our pre-clinical findings to clinical space.
There is considerable synergy with Project 2 of this PPG (led by Dr. Joseph Wu), which seeks to identify risk
factors for ibrutinib-associated cardiotoxicity, as well as Project 3 (PI: Dr. Mark Mercola), which hopes to develop
cardioprotective medications for KI-associated cardiotoxicity. Although the 3 projects will focus on ibrutinib and
other BTK inhibitors, the platforms created can be applied to the many novel covalent and noncovalent KI that
are being approved in oncology.

## Key facts

- **NIH application ID:** 10935739
- **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:** $627,300
- **Award type:** 2
- **Project period:** 2019-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935739

## Citation

> US National Institutes of Health, RePORTER application 10935739, Mechanisms of Cardiotoxicity Associated with Covalent Kinase Inhibitors (2P01HL141084-06). Retrieved via AI Analytics 2026-08-11 from https://api.ai-analytics.org/grant/nih/10935739. Licensed CC0.

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