Cellular ‘death by iron’ may be promising new cancer treatment, scientists say

NEW YORK — There are few positives when it comes to the subject of cancer in general, but there’s actually a “silver lining,” so to speak, within cancer’s own biology. The very same characteristics that allow cancer cells to grow and spread also create opportunities to sabotage and combat cancer. According to researchers at Sloan Kettering, common metabolic changes seen in cancer cells also make those cells vulnerable to a form of cell death known as ferroptosis.

Ferroptosis means death by iron, and is caused by oxidative stress (the buildup of free radicals/corisive chemicals in cells). Those free radicals are produced in the first place as byproducts of using oxygen to burn fuel for energy. Various cancer cells, however, require high levels of energy.

“Genetic mutations that allow cancer cells to cope with oxidative stress make them more resistant to ferroptosis,” Dr. Xuejun Jiang, a cell biologist in the Sloan Kettering Institute, says in a release. “Another way to say this is that without the benefit of those mutations, cancer cells might be very, very sensitive to ferroptosis.”

Testing ferroptosis theory on lab mice

Researchers tested their hypothesis by giving a mixture of two drugs to a group of lab mice. One of those drugs promotes ferroptosis while the other hindered mutation complications. The specific mutation researchers focused on influences a signal-sending pathway known as PI3K-AKT-mTOR, which helps control metabolism. Mutations of this kind are commonly found in cancers, especially the hard-to-treat variety.

At first, tumor cells with these mutations were quite resistant to an experimental ferroptosis-inducing drug. However, when drugs blocking the action of the metabolic pathway to the ferroptosis-inducing drug were added, the cancer cells died. This process was repeated with breast and prostate cancer cells in mouse models, producing the same promising results: “near-complete” tumor destruction.

“These were some of the most significant tumor regressions I’ve ever seen coming from experiments in my lab,” Dr. Jiang says.

‘Exciting way to think about developing new cancer treatments’

How does the mutated PI3K-AKT-mTOR pathway protect cancer cells in the first place? It increases the activity of proteins involved in the production of lipids that surround a call’s outer membrane. Those extra lipids form an additional protective barrier defending against oxidative stress and subsequent ferroptosis. By blocking PI3K-AKT-mTOR, cancer cells are thus vulnerable to ferroptosis.

This research goes hand in hand with an earlier project by Dr. Jiang finding certain cancers have mutations making them more sensitive to ferroptosis, even in the absence of metabolism-changing drugs.

“The key point is that many cancers have genetic alterations that can be exploited to trigger ferroptosis and kill the cells. It’s an exciting way to think about developing new cancer treatments,” he concludes.

The study is published in PNAS.