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Transcriptomics coupled with proteomics reveals osimertinib-induced myocardial mitochondrial dysfunction
Haichao Yang1, Suhua Qiu2, Tiezhu Yao1
1Department of Cardiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050010, China.
Abstract:
Osimertinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used for cancer treatment, can cause significant cardiac toxicity. However, the specific mechanism of osimertinib-induced cardiotoxicity is not fully understood. In this study, we administered osimertinib to mice and neonatal rat ventricular myocytes (NRVMs). We observed significant structural and functional damage to the hearts of these mice, along with a marked increase in cardiac injury biomarkers and accompanying ultrastructural damage to mitochondria. We integrated 4D label-free protein quantification and RNA-Seq methods to analyze the sequencing data of NRVMs under osimertinib treatment (0 and 2.5 μM). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis evidenced that differentially expressed genes (DEGs)and differentially expressed proteins (DEPs) were distinctly enriched for oxidative phosphorylation (OXPHOs). Simultaneously, osimertinib primarily affected the contents of adenosine triphosphate (ATP). Further investigations revealed that osimertinib disrupts the functions of the ATP synthase (complex V), leading to a reduction in ATP production. Taken together, our data demonstrated that osimertinib causes mitochondrial dysfunction, which in turn leads to the onset of cardiac toxicity.
Insights
Osimertinib causes heart damage by disrupting mitochondrial function and reducing ATP production. This study reveals the mechanism behind this cardiotoxicity, offering insights for cancer patients undergoing treatment.
Area of Science:
- Cardiology
- Molecular Biology
- Oncology
Background:
- Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is vital in cancer therapy.
- Cardiac toxicity is a known side effect of osimertinib, but its underlying mechanisms remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms of osimertinib-induced cardiotoxicity.
- To investigate the impact of osimertinib on cardiac mitochondrial function and energy production.
Main Methods:
- Administered osimertinib to mice and neonatal rat ventricular myocytes (NRVMs).
- Utilized 4D label-free proteomics and RNA-sequencing for comprehensive molecular profiling.
- Performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.
Main Results:
- Osimertinib induced significant cardiac structural and functional damage in mice, with elevated injury biomarkers.
- NRVMs treated with osimertinib showed enrichment of differentially expressed genes and proteins in oxidative phosphorylation (OXPHOs).
- Osimertinib disrupted ATP synthase (complex V) function, leading to decreased adenosine triphosphate (ATP) levels and impaired mitochondrial function.
Conclusions:
- Osimertinib-induced cardiotoxicity is mediated by mitochondrial dysfunction.
- Disruption of OXPHOs and subsequent reduction in ATP production are key mechanisms driving cardiac damage.
- Findings provide a mechanistic understanding of osimertinib cardiotoxicity, crucial for managing cancer patients.
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