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.
A new study in Nature Cell Biology reveals that FLT3 inhibitors trigger a unique form of cell death known as ferroptosis in acute myeloid leukemia (AML) cells with FLT3 mutations. This discovery may lead to new, less harmful treatments for AML while potentially overcoming resistance to current therapies. FLT3 mutations are a common driver of AML, and while FLT3 inhibitors can halt cell division and activate apoptosis to kill cancer cells, resistance and relapse remain issues.
The researchers found that FLT3 inhibitors also induce ferroptosis, a process involving lipid peroxidation that causes cell death. This is the first time FLT3 has been linked to ferroptosis. The team discovered that mutant FLT3 proteins activate a protein called GPX4, which normally prevents ferroptosis by reducing lipid peroxidation.
However, FLT3 inhibitors prevent the production of GPX4, leading to cell death through ferroptosis. AML patient data showed that resistant samples often overexpress genes involved in selenoprotein production, including GPX4, which suggests these cells may evade treatment by boosting the selenoprotein pathway. Notably, dietary vitamin E, which counters ferroptosis, significantly reduced the effectiveness of gilteritinib, a common FLT3 inhibitor.
This study highlights ferroptosis as a vulnerability in FLT3-mutant AML and suggests that high vitamin E intake may counteract the drug's efficacy by suppressing ferroptosis.
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