Quizartinib promotes cardiac inflammation that contributes to cardiotoxicity
Y Alshoubaki, R Bernasconi, A Gustinelli, V Gruterich, L Xu, V Lorenz, J Roux, L Wigger, S Calderon, T Pedrazzini, G M KusterAbstract
Introduction
Cardiotoxicity has emerged as a major complication of modern cancer therapies including tyrosine kinase inhibitors (TKIs). Quizartinib, a FLT3 targeting TKI, leads to adverse cardiovascular events in patients; however, the mechanisms underlying this cardiotoxicity remain elusive.
Methods
We combined in vitro and in vivo approaches to investigate the effects of quizartinib on cardiomyocyte homeostasis and cardiac function. In vitro, cultured cardiomyocytes were treated with quizartinib to assess cell viability, metabolic function, and the expression of stress- and inflammation-related genes. In vivo, a murine myocardial infarction (MI) model was used to represent a disease-sensitized myocardium reflective of cancer patients with underlying cardiovascular comorbidities. Mice treated with quizartinib, or vehicle were subjected to MI and cardiac function was assessed by echocardiography and fibrosis up to four weeks post-MI. Bulk RNA sequencing was performed on cardiac tissue collected one-week post-MI and cardiac immune cell populations were quantified by flow cytometry for immune profiling.
Results
Quizartinib treatment reduced cardiomyocyte viability and altered the expression of genes associated with cellular stress, mitochondrial function, and inflammatory signalling. In healthy mice, quizartinib increased cardiac infiltration of innate immune cells, particularly neutrophils and monocytes. Moreover, in the MI model, quizartinib further exacerbated cardiac dysfunction as previously shown as well as cardiac inflammation. Transcriptomic analysis revealed enrichment of interferon signalling and leukocyte migration pathways, alongside down regulation of oxidative phosphorylation, ATP production, and cardiac muscle contraction pathways in quizartinib-treated compared to vehicle-treated infarcted hearts, consistent with more pronounced impairment of metabolic and contractile function.
Conclusions
These findings demonstrate that quizartinib induces cardiomyocyte stress and promotes cardiac inflammation, which together contribute to impaired cardiac repair and more severe dysfunction after injury. This study identifies inflammation as a key mechanistic component of quizartinib-associated cardiotoxicity and provides a rationale for targeting inflammatory pathways to mitigate cardiovascular risk during therapy.