Osimertinib induces reversible cardiac dysfunction through the GATA4-MYLK3-MYL2 axis.

Summary

Using iPSC-cardiomyocytes and a stress-augmented mouse model, the authors show that osimertinib triggers reversible sarcomeric dysfunction via GATA4 dephosphorylation, MYLK3 suppression, and reduced MYL2 phosphorylation. Pharmacologic activation of myosin with omecamtiv prevented dysfunction, suggesting a targeted mitigation strategy for TKI cardiotoxicity.

Key Findings

• Osimertinib caused contractile dysfunction without cell death, inflammation, or fibrosis in a TAC-augmented mouse model.
• Single-nucleus RNA-seq and in vitro assays identified MYLK3 downregulation and reduced MYL2 phosphorylation with sarcomere disarray as central mechanisms.
• GATA4 dephosphorylation linked osimertinib exposure to MYLK3 transcriptional suppression.
• Cardiac dysfunction was reversible upon drug discontinuation.
• The myosin activator omecamtiv prevented osimertinib-induced dysfunction.

Clinical Implications

For patients on osimertinib who develop LV dysfunction, cardiotoxicity may be reversible with drug interruption and potentially preventable with myosin activation. Mechanistic biomarkers (MYLK3/MYL2 signaling) could inform surveillance strategies.

Limitations

• Preclinical study without prospective human validation of the mitigation strategy
• Model (TAC plus osimertinib) may not capture full clinical heterogeneity of patients

Future Directions

Translate findings into early-phase clinical studies testing myosin activation to prevent or reverse TKI cardiotoxicity; validate circulating or imaging biomarkers reflecting the GATA4–MYLK3–MYL2 axis.