# Mitochondrial Dysfunction Underlies the Integrated Stress Response Activation in Ponatinib-Induced Cardiotoxicity

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2023 · $547,212

## Abstract

PROJECT SUMMARY
There has been a significant decline in cancer related mortality, partly due to the emergence of molecular
targeted therapies. Unfortunately, the success of these drugs including tyrosine kinase inhibitors (TKIs) has been
tempered by a concomitant rise in the prevalence of cancer therapies-related cardiotoxicity. Ponatinib, a currently
FDA-approved third-generation TKI, is used to treat chronic myeloid leukemia (CML) patients carrying the
gatekeeper mutation breakpoint cluster region-Abelson (BCR-ABL) T315I. Despite its effectiveness, a
considerable number of patients receiving ponatinib suffers from various cardiac complications. Several studies
have linked ponatinib-induced cardiotoxicity to impaired pro-survival signaling pathways leading to cell death.
However, the molecular signaling pathways leading to these events remain obscure and a better understanding
of how cardiomyocytes respond to ponatinib may provide new insights into novel mitigation therapies. The heart
must adapt to stress conditions that occur as a result of intracellular or extracellular factors. The integrated stress
response (ISR) is one of the circuits responding to stress and serving to restore proteostasis by regulating protein
synthesis, although prolonged ISR activation leads to cell death. Whether the ISR is activated and plays a
protective or detrimental role in ponatinib-induced cardiotoxicity are largely unknown and may represent an
amenable therapeutic target which will be the focus of my current proposal. My preliminary data suggests that
ponatinib causes mitochondrial dysfunction in human induced pluripotent stem cell-derived cardiomyocytes
(hiPSC-CMs). Interestingly, mitochondrial damage appears to trigger activation of the ISR and is mediated by a
kinase called general control non-repressed 2 (GCN2). I also found that inhibition of the ISR using a novel small
molecule called ISR inhibitor (ISRIB) successfully blunted the cardiotoxic effects of ponatinib both in vitro and in
vivo. Hence, the central hypothesis of my proposal is that the ISR pathway which is activated upon sensing
mitochondrial damage plays a pivotal role in mediating ponatinib-induced cardiotoxicity. Aim 1 will investigate
whether activation of GCN2 couples mitochondrial damage to ISR activation upon impaired mitochondrial
reactive oxygen species (ROS) and adenosine triphosphate (ATP) level. Aim 2 will assess whether ponatinib
induces apoptosis and cardiac dysfunction through the GCN2/eIF2α/ATF4 axis. Lastly, aim 3 will explore whether
pharmacological suppression of the ISR even after the onset of ponatinib-induced cardiotoxicity remains
cardioprotective without compromising the efficacy of ponatinib against tumor cells. Taken together, at the
conclusion of these studies, we will have significantly expanded our knowledge by which how ponatinib-induced
mitochondrial dysfunction is sensed to trigger the ISR; whether this activation contributes to cardiac pathology;
and if crosstal...

## Key facts

- **NIH application ID:** 10735043
- **Project number:** 1R01HL164729-01A1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Won Hee Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $547,212
- **Award type:** 1
- **Project period:** 2023-07-18 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10735043

## Citation

> US National Institutes of Health, RePORTER application 10735043, Mitochondrial Dysfunction Underlies the Integrated Stress Response Activation in Ponatinib-Induced Cardiotoxicity (1R01HL164729-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10735043. Licensed CC0.

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