Insights into cancer drug's lethal side effects aim to enhance safety

In a new study, researchers from the University of Illinois Chicago and other universities have identified mechanisms that cause the drug, ponatinib, to harm the heart. They also identified a promising treatment that could reverse this process.

The study published in Circulation Research and conducted with senior author Sang Ging Ong, assistant professor of pharmacology and medicine at UIC, is part of a growing field called cardio-oncology that investigates drugs that shrink tumors but can also cause heart problems.

For some leukemia patients, the only potential chemotherapy option is a drug that also carries a high risk of heart failure. This means that some patients who recover from cancer will end up dying of heart disease brought on by the cure.

“These patients have no other options for treatment,” Ong said, despite the concerns about the drug’s side effects. In fact, ponatinib was discontinued for a few months after its introduction in 2012 because of concerns about heart problems.

The research team aimed to explore how ponatinib interacts with the heart cells that drive contraction. Their findings revealed that ponatinib harms these cells by triggering a mechanism called the integrated stress response.

The underlying process involves a kinase—a type of enzyme that transfers energy—known as the GCN2. The team discovered that ponatinib, although designed to inhibit kinases, surprisingly activates GCN2. This activation initiates the integrated stress response. While this response can be protective for cells, aiming to shield them, it may also result in cell death if the stress persists over time.

The researchers investigated whether blocking the integrated stress response with a small molecule could prevent cell damage during ponatinib treatment in cells and mice.

Their findings indicated that this approach shielded heart cells from the drug's harmful side effects without compromising its ability to combat tumors.

“It protects the heart but at the same time, it still allows us to kill cancer cells,” Ong concluded.

Reference: DOI: 10.1161/CIRCRESAHA.123.323683