Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Mitochondrial dysfunction is a key factor in heart failure.
• The interplay between mitochondrial energy production and signaling pathways is not fully understood.
• Ponatinib, a leukemia drug, is known to cause cardiotoxicity through mitochondrial dysfunction.

Purpose of the Study:

• To investigate the role of the integrated stress response (ISR) in ponatinib-induced cardiotoxicity.
• To elucidate the molecular mechanisms linking mitochondrial stress to ISR activation by ponatinib.

Main Methods:

• Utilized human induced pluripotent stem cell-derived cardiomyocytes and a mouse model.
• Performed proteomic analysis, molecular, and biochemical assays.
• Investigated the impact of ISR inhibition and NAD+ precursor supplementation.

Main Results:

• Ponatinib activated the ISR in cardiac cells, with GCN2 identified as the key kinase.
• Ponatinib inhibited ATP synthase, leading to ATP deficits that triggered ISR activation.
• Decreased ATP levels facilitated direct activation of GCN2 by ponatinib.
• ISR inhibition protected cardiomyocytes and attenuated cardiac dysfunction in mice without affecting ponatinib's anti-tumor effects.

Conclusions:

• Neutralizing ISR hyperactivation can prevent or reverse ponatinib-induced cardiotoxicity.
• Compromised ATP production potentiates GCN2-mediated ISR activation, with implications for various cardiac diseases.
• Ponatinib directly activates GCN2, independent of its ATP-competitive kinase inhibition.