Findings may help reduce cardiotoxicity of ponatinib for chronic myeloid leukemia
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Researchers have discovered the mechanisms by which the chemotherapy drug ponatinib harms the heart.
The findings highlight how ponatinib (Iclusig, Takeda) — one of three drugs approved in the United States for treatment of chronic myeloid leukemia — damages heart cells by activating a process called integrated stress response (ISR).
Although ponatinib is a kinase inhibitor, it activates GCN2, an enzyme involved in energy transfer. This switches on the ISR, which is intended to protect cells but can contribute to prolonged stress that leads to their death, according to researcher Sang-Ging Ong, PhD, assistant professor in the department of pharmacology at The University of Illinois Chicago, and colleagues.
Healio spoke with Ong about his team’s discovery and how it might impact the use of ponatinib for treatment of CML.
Healio: Can you briefly describe ponatinib’s role in CML treatment and its safety profile?
Ong: Ponatinib is used as a third-line inhibitor for patients with CML. These patients develop resistance against at least two other tyrosine kinase inhibitors before they are put on ponatinib.
The most common adverse effects associated with ponatinib are thrombotic events, where blood vessels get stuck or develop arterial occlusions. Some patients develop hypertension. Occasionally, patients die of heart failure. In this study, we focused on the effects of ponatinib on cardiomyocytes. Clinically, however, we more often see its effects on the vasculature.
Healio: What did you find in terms of ponatinib’s cardiotoxic mechanism?
Ong: We knew this drug would cause cardiotoxic effects on cardiomyocytes. We took blood cells from volunteers and converted them into plenipotent stem cells. Using specific chemicals, we differentiated them into cardiac cells. We sent cells treated with his drug to a proteomic call center and they did a high-throughput proteomic platform.
This proteomic platform showed there was a signature of activation of ISR. This is a specific cellular response to stress, and it can be both good and bad. When it’s activated for a short period of time, it’s good because it enables cells to adapt to stress. In this particular case, however, we found that activation of the ISR is bad for the cells in the long term. I believe that if you activate the ISR for too long, it causes damage to the cells.
Healio: Can this effect be reversed?
Ong: We found that if we block ISR with a small molecule called esterase, we can rescue the cells from the properties of ponatinib. Esterase — a small ISR inhibitor molecule — has been shown to inhibit ISR and has been typically used in studies involving the brain. Now we are showing that if we block the ISR, both in vitro and in mouse models, we can protect the heart against the detrimental effects of ponatinib.
Healio: What are the potential implications of your findings?
Ong: We have some in vitro data showing that when we treat cancer cells receiving ponatinib in the presence of esterase, it does not prevent ponatinib from killing the cancer cells. This is important in the sense that we can potentially combine the use of ponatinib with the small molecule inhibitor esterase, which can protect the cardiac cells while still enabling ponatinib to kill tumor cells. If anything, we see synergistic effects in terms of esterase promoting the cancer-killing effects of ponatinib. If esterase prevented ponatinib from killing tumor cells, it would be a no-go to try to use the esterase. Luckily, we don’t see this happening.
Healio: What are the next steps in research?
Ong: We have shown that esterase protects cardiomyocytes against ponatinib but, as I mentioned previously, ponatinib affects the vasculature, as well. We’re expending our studies to see if esterase is protective of vasculatures apart from the cardiomyocytes themselves.
Reference:
For more information:
Sang-Ging Ong, PhD, can be reached at sangging@uic.edu.
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