For some leukemia patients, the only available treatment option is a medication that has a substantial risk of heart failure. This means that some cancer patients who recover will eventually die of heart disease caused by the cure.
In a new study, researchers from the University of Illinois Chicago and other universities discovered pathways that lead the medicine ponatinib to injure the heart. They also discovered a viable therapy that could reverse the process. The article, co-authored by senior author Sang Ging Ong, an assistant professor of pharmacology and medicine at UIC, is published in Circulation Research. The study is part of a developing discipline called cardio-oncology, which looks into drugs that decrease tumors but also cause cardiac difficulties.
While there are three options of drugs for treating chronic myeloid leukemia, many patients are resistant to the other two, leaving ponatinib as their only choice.
The researchers were interested in understanding the interaction between ponatinib and the heart cells responsible for contraction. They discovered that ponatinib damages these cells by activating a process known as the integrated stress response.
“These patients have no other options for treatment,” Ong said, despite the concerns about the drug’s side effects. Ponatinib was pulled from the market for a few months after its introduction in 2012 because of concerns about heart problems.
The researchers were interested in understanding the interaction between ponatinib and the heart cells responsible for contraction. They discovered that ponatinib damages these cells by activating a process known as the integrated stress response.
The mechanism for this is related to the functioning of a kinase — an enzyme involved in energy transfer – called GCN2. The researchers found that ponatinib, despite being a kinase inhibitor, actually activates GCN2, which in turn switches on the integrated stress response. While this response isn’t always a bad thing — its purpose is to protect cells — it can also lead to their death under prolonged stress.
To determine whether this reaction was harmful to the cells, the researchers investigated what would happen if they employed a tiny chemical to inhibit the integrated stress response in both cells and mice during ponatinib treatment. They discovered that the treatment protected cardiac cells from the drug’s detrimental side effects while maintaining ponatinib’s tumor-fighting efficiency.
“It protects the heart but at the same time, it still allows us to kill cancer cells,” Ong went on to say.
Ong stated that more research is needed to see whether this preventative approach would be effective in humans. The pathways they discovered are crucial in other heart illnesses, which could lead to further research into how to protect cells from various circumstances.
