FLT3 inhibitors trigger ferroptosis, exposing new weakness in acute myeloid leukemia

A study published in Nature Cell Biology reports a new vulnerability in acute myeloid leukemia (AML) that might lead to novel therapies to treat the cancer while minimizing harm to normal cells. Researchers at Baylor College of Medicine and collaborating institutions studied a new mechanism by which drugs that neutralize FLT3 mutations work.

“FLT3 mutations are one of the most common genetic drivers of AML. Other researchers have shown that inhibiting FLT3 stops AML cells from dividing and kills them by activating a self-destruct mechanism called apoptosis,” said corresponding author Dr. Daisuke Nakada, Henry and Emma Meyer Professor of Molecular and Human Genetics at Baylor.

“But like many other cancer therapies, resistance to FLT3 inhibitors and relapse are common. We explored the possibility that FLT3 inhibitors also lead to cancer death in a different way that we might be able to leverage to overcome therapy resistance.”

Ferroptosis emerges as a second route

The team worked with a combination of mouse models and cell-line experiments, as well as patient-derived AML samples grown in animal models. They discovered that FLT3 inhibitors also kill AML cells by triggering ferroptosis.

“This mechanism involves lipid peroxidation—oxygen damages lipids in cells in ways that cause cell death,” said Nakada, a member of Baylor’s Dan L Duncan Comprehensive Cancer Center and a CPRIT Scholar. “This is the first time FLT3 has been connected to ferroptosis.”

How mutant FLT3 blocks cell death

Digging deeper into the mechanism, Nakada and his colleagues found that mutant FLT3 proteins in AML cells activate a protein called GPX4, which in turn prevents ferroptosis.

“GPX4 belongs to the selenoprotein family known to be involved in reducing lipid peroxidation,” Nakada said. “FLT3 inhibitors prevent the production of selenoproteins, including GPX4. Then, cancer cells do not have enough GPX4 to prevent lipid peroxidation and die.”

Resistance and diet may shape response

Data from AML patients revealed that leukemia samples resistant to the FLT3 inhibitor gilteritinib often overexpress genes involved in selenoprotein production. This suggests that one way leukemia cells could escape treatment is by boosting the selenoprotein pathway.

Nakada and his colleagues also found that dietary vitamin E, which attenuates ferroptosis, can markedly reduce the efficacy of gilteritinib. This study highlights ferroptosis as a vulnerability in FLT3-mutant AML and suggests that a high intake of vitamin E may compromise the efficacy of FLT3 inhibitors by suppressing ferroptosis.

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Sadie Harley

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Robert Egan

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