Ponatinib, But Not the New Abl-Kinase Inhibitor Asciminib, Activates Platelets, Leukocytes, and Endothelial Cell TNF Signaling to Induce Atherosclerotic Plaque Inflammation, Myocardial Infarction, and Stroke.

Summary

Ponatinib uniquely activates endothelial TNFR2 signaling, leukocytes, and platelets, driving thromboinflammation, plaque destabilization, and death from MI and stroke in mice, whereas asciminib lacks these effects. Pharmacologic TNF/TNFR pathway inhibition prevented ponatinib-induced vascular activation and events, nominating both a safer Abl inhibitor (asciminib) and TNFR2 signaling as actionable cardio-oncology targets.

Key Findings

• Ponatinib, but not asciminib or imatinib, increased endothelial TNFR expression, adhesion molecules (P-selectin, ICAM1, VCAM1), and activated TNFR2 signaling.
• In murine models, ponatinib increased leukocyte rolling/adhesion, platelet-leukocyte aggregates, plaque necrotic core and inflammation, accelerating death from MI and stroke.
• Pharmacologic TNFR inhibition or TNFR2 knockdown blocked endothelial activation, reduced plaque inflammation, and prevented MI/stroke in vivo.

Clinical Implications

Prefer asciminib over ponatinib when oncologically appropriate; consider vigilant cardiovascular risk assessment in ponatinib-treated patients. TNF/TNFR pathway modulation may emerge as a cardioprotective strategy pending clinical validation.

Limitations

• Preclinical models may not fully recapitulate human cardio-oncology toxicity landscapes
• No randomized clinical data on TNFR blockade as cardioprotection in ponatinib-treated patients

Future Directions

Prospective clinical studies comparing asciminib vs ponatinib cardiovascular outcomes; early-phase trials testing selective TNFR2 or TNF pathway modulation as cardioprotection in high-risk patients.