Multiscale profiling of tyrosine kinase inhibitor cardiotoxicity reveals mechanosensitive ion channel PIEZO1 as cardioprotective.

Summary

Using patient-specific iPSC-derived endothelial cells and a mouse model of sunitinib-induced hypertension, the authors identify endothelial mechanotransduction via the mechanosensitive channel PIEZO1 as a key determinant of TKI vascular/cardiac injury. PIEZO1 signaling was downregulated by TKI exposure; preserving or augmenting PIEZO1-mediated signaling mitigated hypertension and vascular/cardiac dysfunction in vivo.

Key Findings

• Patient-specific iPSC-derived endothelial cells and a mouse TKI-hypertension model implicated impaired endothelial mechanotransduction in sunitinib toxicity.
• Mechanosensitive channel PIEZO1 signaling was downregulated by TKI exposure.
• Preserving/augmenting PIEZO1 signaling mitigated hypertension and vascular/cardiac dysfunction in vivo.

Clinical Implications

PIEZO1 signaling may be a target for preventing or attenuating hypertension and cardiotoxicity in patients receiving VEGFR-TKIs. This supports biomarker development (endothelial mechanotransduction readouts) and co-therapy trials aimed at preserving endothelial mechanosensing during TKI therapy.

Limitations

• Abstracted results are truncated; detailed molecular mediators and breadth across different TKIs are not fully reported here
• Preclinical models; clinical efficacy and safety of PIEZO1-targeted interventions remain untested

Future Directions

Test PIEZO1-modulating strategies as co-therapies in TKI-treated patients; validate endothelial mechanotransduction biomarkers; expand to additional TKIs and cancer indications.