Bernasconi, Riccardo. Lnc-ing cardiotoxicity to cancer drugs: role of long non-coding RNAs in TKI-related cardiotoxicity. 2024, Doctoral Thesis, University of Basel, Faculty of Science.
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Abstract
Cancer therapy has increased the lifespan of cancer patients worldwide. Nevertheless, the improved survival has uncovered a rising number of cardiovascular adverse events associated with or directly caused by cancer treatment. Novel targeted therapies such as small molecule tyrosine kinases inhibitors (TKIs) have been shown to be cardiotoxic, especially in the already heart-diseased population. Secondary cardiovascular events might be caused by on- and/or off-target toxicities due to the inhibition of these important receptors also expressed in the heart.
The fms-like tyrosine kinase 3 (Flt3) is a tyrosine kinase receptor mainly expressed in early hematopoietic progenitor cells and its mutation leads to constitutive activation that drives acute myeloid leukemia. The lab previously demonstrated a cytoprotective role of Flt3 activation after myocardial infarction (MI) in mice by injecting intramyocardially recombinant Flt3-ligand, which resulted in improved post-MI remodeling and function. We also found that the Flt3-targeting TKI quizartinib increases apoptotic cell death and worsens maladaptive remodeling after MI. Currently, long non-coding RNAs (lncRNAs), the largest class of non-coding RNAs, have emerged as master regulators of the gene regulatory network and they play a major role in cardiovascular disease pathophysiology. Through their cell type specificity and their actions on epigenetic, post-transcriptional and translational processes, they represent attractive molecules for therapeutic targeting.
Our research showed that the hidden cardiotoxicity of quizartinib, which manifests in the infarcted heart, is associated with a distinct expression pattern of lncRNAs. This altered transcriptomic landscape unveils a pool of possible therapeutic targets for cardioprotection. We identified a novel candidate lncRNA XLOC_044469, which was enriched in cardiac fibroblast, upregulated in quizartinib-treated infarcted hearts and which highly correlated with cardiac dysfunction and remodeling parameters. It was found to be localized within the transcription factor Basonuclin 2 (Bnc2) locus, which similarly showed upregulation in quizartinib-treated infarcted mouse hearts and strong correlation with cardiac dysfunction and remodeling parameters. Furthermore, the apparent locus conservation in humans could harbor translational value, which could be explored for therapeutic targeting. Finally, quizartinib-treated infarcted hearts showed a distinct expression pattern of protein-coding genes, with enrichment of gene sets related to cardiac contractility and energy handling. Via a mitochondrial activity assay, we demonstrated alterations in cellular respiration and ATP production of cardiomyocytes in response to quizartinib in a dose-dependent manner.
Although many cancer therapies are already known for their cardiovascular side effects, more studies investigating cancer drug-related cardiotoxicity are necessary, since most clinical trials exclude the most vulnerable patients, who have cardiovascular risk factors or underlying cardiac diseases. As we observed in our study, cardiovascular toxicity might only happen in the already diseased heart. In this regard, the lncRNA landscape may harbor great potential for the discovery of future therapeutic targets for cardioprotection against TKI-related cardiotoxicities.
The fms-like tyrosine kinase 3 (Flt3) is a tyrosine kinase receptor mainly expressed in early hematopoietic progenitor cells and its mutation leads to constitutive activation that drives acute myeloid leukemia. The lab previously demonstrated a cytoprotective role of Flt3 activation after myocardial infarction (MI) in mice by injecting intramyocardially recombinant Flt3-ligand, which resulted in improved post-MI remodeling and function. We also found that the Flt3-targeting TKI quizartinib increases apoptotic cell death and worsens maladaptive remodeling after MI. Currently, long non-coding RNAs (lncRNAs), the largest class of non-coding RNAs, have emerged as master regulators of the gene regulatory network and they play a major role in cardiovascular disease pathophysiology. Through their cell type specificity and their actions on epigenetic, post-transcriptional and translational processes, they represent attractive molecules for therapeutic targeting.
Our research showed that the hidden cardiotoxicity of quizartinib, which manifests in the infarcted heart, is associated with a distinct expression pattern of lncRNAs. This altered transcriptomic landscape unveils a pool of possible therapeutic targets for cardioprotection. We identified a novel candidate lncRNA XLOC_044469, which was enriched in cardiac fibroblast, upregulated in quizartinib-treated infarcted hearts and which highly correlated with cardiac dysfunction and remodeling parameters. It was found to be localized within the transcription factor Basonuclin 2 (Bnc2) locus, which similarly showed upregulation in quizartinib-treated infarcted mouse hearts and strong correlation with cardiac dysfunction and remodeling parameters. Furthermore, the apparent locus conservation in humans could harbor translational value, which could be explored for therapeutic targeting. Finally, quizartinib-treated infarcted hearts showed a distinct expression pattern of protein-coding genes, with enrichment of gene sets related to cardiac contractility and energy handling. Via a mitochondrial activity assay, we demonstrated alterations in cellular respiration and ATP production of cardiomyocytes in response to quizartinib in a dose-dependent manner.
Although many cancer therapies are already known for their cardiovascular side effects, more studies investigating cancer drug-related cardiotoxicity are necessary, since most clinical trials exclude the most vulnerable patients, who have cardiovascular risk factors or underlying cardiac diseases. As we observed in our study, cardiovascular toxicity might only happen in the already diseased heart. In this regard, the lncRNA landscape may harbor great potential for the discovery of future therapeutic targets for cardioprotection against TKI-related cardiotoxicities.
Advisors: | Kuster Pfister, Gabriela |
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Committee Members: | Schär, Primo Leo and Diviani, Dario |
Faculties and Departments: | 03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Myocardial Research (Kuster Pfister) 05 Faculty of Science |
UniBasel Contributors: | Kuster Pfister, Gabriela and Schär, Primo Leo |
Item Type: | Thesis |
Thesis Subtype: | Doctoral Thesis |
Thesis no: | 15578 |
Thesis status: | Complete |
Number of Pages: | 184 |
Language: | English |
Identification Number: |
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edoc DOI: | |
Last Modified: | 25 Jan 2025 05:30 |
Deposited On: | 24 Jan 2025 11:19 |
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