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Ponatinib-induced cardiotoxicity: delineating the signalling mechanisms and potential rescue strategies
Anand P Singh1, Michael S Glennon1,2, Prachi Umbarkar1
1Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2220 Pierce Ave, PRB#348A, Nashville, TN, USA.
Aims:
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myelogenous leukaemia (CML). However, cardiotoxicity of these agents remains a serious concern. The underlying mechanism of these adverse cardiac effects is largely unknown. Delineation of the underlying mechanisms of TKIs associated cardiac dysfunction could guide potential prevention strategies, rescue approaches, and future drug design. This study aimed to determine the cardiotoxic potential of approved CML TKIs, define the associated signalling mechanism and identify potential alternatives.
Methods And Results:
In this study, we employed a zebrafish transgenic BNP reporter line that expresses luciferase under control of the nppb promoter (nppb:F-Luciferase) to assess the cardiotoxicity of all approved CML TKIs. Our in vivo screen identified ponatinib as the most cardiotoxic agent among the approved CML TKIs. Then using a combination of zebrafish and isolated neonatal rat cardiomyocytes, we delineated the signalling mechanism of ponatinib-induced cardiotoxicity by demonstrating that ponatinib inhibits cardiac prosurvival signalling pathways AKT and extra-cellular-signal-regulated kinase (ERK), and induces cardiomyocyte apoptosis. As a proof of concept, we augmented AKT and ERK signalling by administration of Neuregulin-1β (NRG-1β), and this prevented ponatinib-induced cardiomyocyte apoptosis. We also demonstrate that ponatinib-induced cardiotoxicity is not mediated by inhibition of fibroblast growth factor signalling, a well-known target of ponatinib. Finally, our comparative profiling for the cardiotoxic potential of CML approved TKIs, identified asciminib (ABL001) as a potentially much less cardiotoxic treatment option for CML patients with the T315I mutation.
Conclusion:
Herein, we used a combination of in vivo and in vitro methods to systematically screen CML TKIs for cardiotoxicity, identify novel molecular mechanisms for TKI cardiotoxicity, and identify less cardiotoxic alternatives.
Insights
Tyrosine kinase inhibitors (TKIs) used for chronic myelogenous leukaemia (CML) can cause heart damage. This study found ponatinib is highly cardiotoxic by inhibiting AKT and ERK pathways, while asciminib shows less cardiotoxicity.
Area of Science:
- Cardiology
- Oncology
- Pharmacology
Background:
- Tyrosine kinase inhibitors (TKIs) have transformed chronic myelogenous leukaemia (CML) treatment.
- Cardiotoxicity is a significant adverse effect of TKIs, with underlying mechanisms poorly understood.
- Understanding TKI cardiotoxicity is crucial for developing safer treatments and drug design.
Purpose of the Study:
- To evaluate the cardiotoxic potential of approved CML TKIs.
- To elucidate the signaling pathways involved in TKI-induced cardiotoxicity.
- To identify potentially safer TKI alternatives for CML patients.
Main Methods:
- Utilized a zebrafish transgenic BNP reporter line for in vivo cardiotoxicity screening of CML TKIs.
- Investigated ponatinib-induced cardiotoxicity using zebrafish and isolated neonatal rat cardiomyocytes.
- Assessed the role of AKT, ERK, and fibroblast growth factor signaling pathways.
Main Results:
- Identified ponatinib as the most cardiotoxic TKI in the screen.
- Demonstrated ponatinib inhibits cardiac AKT and ERK prosurvival pathways, leading to cardiomyocyte apoptosis.
- Showed that augmenting AKT/ERK signaling with Neuregulin-1β protected against ponatinib cardiotoxicity.
- Confirmed ponatinib cardiotoxicity is not mediated by fibroblast growth factor inhibition.
- Identified asciminib (ABL001) as a potentially less cardiotoxic option for T315I-mutated CML.
Conclusions:
- Systematically screened CML TKIs for cardiotoxicity using in vivo and in vitro models.
- Identified inhibition of AKT and ERK signaling as a key mechanism in ponatinib-induced cardiotoxicity.
- Asciminib emerges as a promising, less cardiotoxic therapeutic alternative for CML.
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