A study published in Nature Cell Biology reports a newly discovered vulnerability in acute myeloid leukemia that may lead to therapies targeting cancer cells while minimizing harm to normal cells, according to an Aug. 7 report.
Researchers at Baylor College of Medicine and collaborating institutions studied how drugs that neutralize mutations of the enzyme FLT3 affect acute myeloid leukemia (AML) cells. The team used mouse models, cell line experiments, and patient-derived AML samples grown in animal models. They found 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."
Nakada and colleagues further determined that mutant FLT3 proteins activate GPX4, a protein which prevents ferroptosis by reducing lipid peroxidation. "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." Data from patients showed that AML samples resistant to the FLT3 inhibitor gilteritinib often overexpress genes related to selenoprotein production.
The study also found dietary vitamin E can reduce the effectiveness of gilteritinib by attenuating ferroptosis: "This study highlights ferroptosis as a vulnerability in FLT3-mutant AML and suggests that consuming high amounts of vitamin E may compromise the efficacy of FLT3 inhibitors by suppressing ferroptosis," Nakada said.
Other contributors include Minhua Li, Yudan Zhu, Yuki Kageyama, Ken Furudate, Ayumi Kitano, Taotao Tan, Mengdie Feng, Jing Zhou, Tao Wang, Robert J. Taylor, Alexandra M. Stevens, Md. Abul Hassan Samee, Jeffrey A. Magee and Koichi Takahashi from Baylor College of Medicine; University of Texas MD Anderson Cancer Center – Houston; Texas A&M University – College Station; and Washington University School of Medicine – St. Louis.
