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The role of the cancer kinome in the healthy and injured heart: focus on Flt3 and Plk2

Monogiou Belik, Daria. The role of the cancer kinome in the healthy and injured heart: focus on Flt3 and Plk2. 2020, Doctoral Thesis, University of Basel, Faculty of Science.

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Abstract

In this work we investigated the effects of the Fms-like tyrosine kinase 3 (Flt3) targeting inhibitor quizartinib in the infarcted mouse heart. Flt3 is a transmembrane receptor tyrosine kinase (TK) that is involved in the regulation of normal hematopoiesis. Activating mutations of Flt3 account for 30% of all cases of acute myeloid leukemia (AML). Therefore, Flt3- targeting inhibition through pharmacological means can be applied for AML treatment. However, due to the homology among kinase receptors in both malignant and healthy cells, those treatments may lack specificity and interfere with other signaling pathways that are also important for cardiac homeostasis and function, leading to cardiotoxicity.
Our laboratory previously identified that Flt3-signaling has a cytoprotective role during ischemic cardiac injury, such as myocardial infarction (MI). Given that Flt3 is a target for cancer therapy and plays an important cytoprotective role during MI, we investigated the effects of pharmacological inhibition of Flt3 in the heart upon MI. Specifically, we studied the role of quizartinib, a second-generation Flt3 inhibitor with high selectivity and an efficient single agent in clinical trials in patients with AML.
We showed that quizartinib, administered to five week old male mice for three weeks prior to induction of MI, did not affect cardiac dimensions or function after one week post-MI in comparison to vehicle. However, apoptotic cell death was significantly enhanced in both the infarct border zone and the remote myocardium of quizartinib-treated vs. vehicle-treated mice. No significant differences were observed in cardiomyocyte size or fibrotic area. A three week post-MI analysis showed cardiac dilation and decline in cardiac function to be more persistent in quizartinib-treated infarcted mice vs. quizartinib-treated sham mice than in vehicle-treated infarcted mice vs. their corresponding sham. Immunohistochemical assays showed no differences in apoptosis or fibrosis after three weeks between quizartinib and vehicle-treated mice. Comparable studies in Flt3-receptor deficient mice, which did not present differences in cardiac function and remodeling upon quizartinib administration, suggested that these effects are related to the inhibition of Flt3 and that the drug appears to have on-target toxicity. In vitro experiments showed that quizartinib decreased cell viability and increased apoptosis in H9c2 cells in a dose dependent manner. In addition, quizartinib at both high (20μM) and low concentrations (5μM) augmented H2O2-induced cell death and apoptosis beyond additive degree. In conclusion, this work showed that short-term pharmacological inhibition of Flt3 decreases cell viability and potentiates hypoxic cardiomyocyte death in vitro and in vivo.
Due to more frequent and widespread use of TK targeting cancer therapies, there is an increasing need to more thoroughly investigate and comprehend the role of the targeted TK in heart function, in order to foresee any potential adverse effect or toxicity. In this study we explored cardiac structure and function upon ischemic injury in combination with a potent TK targeting cancer treatment. Patients with underlying cardiac disease are often excluded from clinical trials, hence safety of such therapies in these patients is unknown. The findings of our study raise concerns regarding potential cardiotoxicity of quizartinib (or Flt3-targeting in general) in patients with underlying ischemic heart disease.
Advisors:Kuster Pfister, Gabriela
Committee Members:Handschin, Christoph and Schär, Primo Leo
Faculties and Departments:02 Faculty of Law > Departement Rechtswissenschaften > Fachbereich Privatrecht > Ordinariat Privatrecht, insb. Gesellschafts- und Rechnungslegungsrecht (Handschin)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Myocardial Research (Kuster Pfister)
03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Molecular Genetics (Schär)
UniBasel Contributors:Kuster Pfister, Gabriela and Handschin, Christoph and Schär, Primo Leo
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14790
Thesis status:Complete
Number of Pages:157
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss147901
edoc DOI:
Last Modified:03 Sep 2022 04:30
Deposited On:02 Sep 2022 08:55

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