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A Ponatinib-Associated Transcriptomic Signature: Implications for Cardiovascular Toxicity
Joonho Kong1, Jaeyeon Jang2, Jee Hyun Kong2
1Department of Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea.
International Journal of Molecular Sciences
|May 13, 2026
Summary
Ponatinib treatment alters gene expression in cancer cells and cardiomyocytes, revealing a unique transcriptomic signature linked to cardiovascular toxicity. This signature differs from imatinib and highlights key genes for further research.
Area of Science:
- Genomics
- Cardiovascular Pharmacology
- Molecular Biology
Background:
- Ponatinib, a BCR::ABL1 inhibitor, exhibits anti-leukemic effects but poses cardiovascular risks.
- The precise molecular mechanisms underlying ponatinib-induced cardiotoxicity, particularly at the transcriptome level, require further elucidation.
Purpose of the Study:
- To define a transcriptomic signature associated with ponatinib treatment.
- To investigate the mechanistic implications of this signature in cardiovascular toxicity using public RNA sequencing datasets.
- To identify overlapping gene expression patterns between cancer cell lines and cardiomyocytes treated with ponatinib.
Main Methods:
- Utilized two RNA sequencing datasets (GSE186341 and GSE217421) comprising cancer cell lines and induced pluripotent stem cell (iPSC)-derived cardiomyocytes.
- Applied principal component analysis (PCA) and k-means clustering for subgroup identification.
- Employed DESeq2 and fixed-effect meta-analysis to identify differentially expressed genes (DEGs) and pooled treatment effects.
- Performed cross-dataset analysis to identify overlapping gene sets between the two datasets.
Main Results:
- Identified 2639 meta-analytically differentially expressed genes (meta-DEGs) in cancer cell lines.
- Found 81 overlapping genes differentially expressed in both cancer cell lines and iPSC-derived cardiomyocytes after ponatinib treatment.
- Observed no overlap in these 81 genes when analyzing imatinib treatment under the same framework.
- Highlighted cardiotoxicity-relevant genes involved in ion handling, metabolic regulation, stress signaling, and mitochondrial homeostasis.
Conclusions:
- Defined a distinct ponatinib-associated transcriptomic signature.
- Nominated specific transcript-level candidates for further investigation into ponatinib-induced cardiotoxicity.
- Demonstrated the utility of cross-dataset analysis in identifying conserved molecular responses to targeted therapies.
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