Researchers at NYU Langone Health said Wednesday that an experimental drug that blocks a key protein can trigger a form of self-destruction in lung cancer cells and dramatically slow tumor growth in mice, a finding published Nov. 5 in the journal Nature.
The team reported that inhibiting ferroptosis suppressor protein 1, or FSP1, unleashes ferroptosis, a non-apoptotic cell-death process driven by iron-dependent lipid peroxidation, and reduced tumor growth by as much as 80% in mouse models of lung adenocarcinoma, the most common lung cancer among people who have never smoked. The study also found that treatment with an FSP1 inhibitor, called icFSP1, improved the survival of tumor-bearing mice nearly to the level seen when FSP1 was genetically deleted in tumors.
“This first test of a drug that blocks ferroptosis suppression highlights the importance of the process to cancer cell survival and paves the way for a new treatment strategy,” said senior author Thales Papagiannakopoulos, Ph.D., an associate professor of pathology at the NYU Grossman School of Medicine.
Novel clinical therapies for lung cancer patients
Ferroptosis is caused by the buildup of reactive oxygen species that damage lipids in cell membranes. Normal cells and cancer cells use enzymes such as glutathione peroxidase 4 (GPX4) and FSP1 to prevent lethal lipid peroxidation. The NYU team found that lung tumors rely heavily on FSP1 in vivo and that blocking FSP1 allows oxidative damage to accumulate and kill cancer cells.
In genetically engineered mice, tumor-specific deletion of the FSP1 gene markedly increased cancer cell death and produced significantly smaller tumors. The researchers showed similar results across multiple preclinical models, including human cell-line xenografts and a patient-derived xenograft, indicating the effect was not limited to a single genetic background or tumor lineage. Lead author Katherine Wu, an M.D./Ph.D. student in the Papagiannakopoulos laboratory, said the work positions FSP1 as a promising therapeutic target. “We aim to translate these findings from the lab into novel clinical therapies for cancer patients,” she said.
The paper describes a series of complementary experiments that linked FSP1 loss to increased oxidized phospholipids in tumors and demonstrated that restoring antioxidant defenses, by genetic deletion of the lipid-incorporating enzyme ACSL4, by dietary vitamin E supplementation, or by treatment with the radical-trapping antioxidant LIP1, rescued tumor growth. Those rescue experiments bolster the conclusion that ferroptosis, rather than other forms of cell death, underlies the tumor suppression seen with FSP1 inhibition.
Further work needed
The investigators also compared FSP1 with GPX4, a better-known ferroptosis regulator. GPX4 is essential in many normal tissues, and germline Gpx4 loss is not compatible with life, the authors noted, raising safety concerns for GPX4-targeted therapies. By contrast, Fsp1 knockout mice are viable, and the study showed that elevated FSP1 expression in human lung adenocarcinomas correlated with more advanced disease and poorer survival, making FSP1 a potentially more selective and safer target.
To test a druggable approach, the team used icFSP1, a recently developed inhibitor with in vivo stability. In a hybrid model expressing human FSP1 in mouse tumors, icFSP1 treatment reduced tumor growth and extended overall survival. Co-administration of LIP1, which blocks lipid peroxidation, abrogated the antitumor benefit of icFSP1, supporting the idea that the drug acts by inducing ferroptosis in tumor cells.
The authors cautioned that most data are preclinical and that further work is needed to optimize FSP1 inhibitors and evaluate safety. NYU Langone editors noted the study was edited by Sadie Harley and reviewed by Robert Egan. Lung cancer is the leading cause of cancer death worldwide, and lung adenocarcinoma accounts for roughly 40% of cases among nonsmokers, the researchers said. The study’s authors suggested future research will seek to refine FSP1 inhibitors and test whether ferroptosis induction could be effective against other solid tumors, including pancreatic cancer.
See all the latest news from Greece and the world at Greekreporter.com. Contact our newsroom to report an update or send your story, photos and videos. Follow GR on Google News and subscribe here to our daily email!
