Mechanisms of tyrosine kinase inhibitor cardiotoxicity
Description: Tyrosine kinase inhibitors (TKIs) inhibit oncogenic kinases that are responsible for tumor development and growth. Many of these kinases are protective in the heart, in particular in cardiovascular disease, when their cardiac expression is upregulated and they are needed for compensatory processes. Even if tolerated well in heart-healthy individuals, inhibition of such kinases in patients with cardiovascular co-morbidities can therefore be harmful (“hidden cardiotoxicity”). Understanding of the cellular and molecular mechanisms of overt or hidden TKI cardiotoxicity is limited and specific cardioprotective strategies are lacking. We previously identified fms-like tyrosine kinase 3 (Flt3), a target of TKIs used for treatment of acute myeloid leukemia and solid tumors, as being protective after myocardial infarction (MI) in mice. Our preliminary data now show that the Flt3-targeting TKI quizartinib alters gene expression and worsens remodeling and function of infarcted hearts. In this project we will (i) investigate whether and how cardiotoxicity differs between different groups of TKIs and how it is affected by cardiovascular co-morbidities, (ii) define the roles of different cellular compartments and the molecular mechanisms of TKI cardiotoxicity, and (iii) test strategies of cardioprotection by interfering with identified (and ideally shared) mechanisms. Preclinical studies addressing the mechanisms of TKI toxicity, in particular in models of cardiovascular comorbidities, are urgently needed. Such research will allow to identify targets for cardioprotection under TKI therapy, which will particularly benefit the most vulnerable patients, and may help uncover regulatory mechanisms in the heart that could be exploited for treatment of cardiovascular disease of other cause.
Amount: CHF 720,000
Funding type: research
Funder scheme: Project funding
Start date: 2024-05-01
End date: 2028-04-30
Investigator: Kuster Pfister, Gabriela
Institution: University of Basel – BS
Funded outputs count: 5
Funder award ID: 219250
OpenAlex ID: G2498688862