New study offers a potential way to overcome cancer resistance to treatment

Researchers from the University of California San Francisco (UCSF) have shown that the enzyme GPX4 could be targeted to prevent acquired drug resistance. The discovery would improve cancer treatment in the future.

The study, titled "Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition," appears in the famous journal Nature. Dr. Matthew Hangauer, an assistant researcher at the UCSF, is the first author. In addition to UCSF, the study also involves the Broad Institute, DataSet Analysis LLC, and The Translational Genomics Research Institute.

Drug resistance is a great challenge in cancer treatment. Some scientists believe that drug resistance is due to genetic evolution in cancer cells. A small portion of cancer cells have specific mutations or obtain novel mutations that help them escape the toxic effects of therapeutic agents. These cancer cells survive and finally cause recurrence, while others are killed by therapeutic agents.

But, recent studies suggested the presence of a new mechanism of drug resistance, which is not directly associated with genetic mutations. Simply put, a subset of cancer cells enter a dormant or persister state so that they can tolerate the strong pressure induced by anti-cancer drugs. After a certain period of time, these dormant cancer cells may become active and drive cancer growth. A lot of efforts have been made to find out the weak points of these drug-tolerant cancer persister cells.

Dr. Hangauer and co-workers, along with collaborators at the Broad Institute, previously discovered that "persister cells undergo a switch to mesenchymal gene expression and are uniquely susceptible to inhibition of the phospholipid hydroperoxidase GPX4." Additional evidence indicates that cancer cells in this high mesenchymal therapy-resistant state are dependent on GPX4 for survival.

For the current study, Dr. Hangauer's team further investigated how GPX4 inhibition would influence cancer cells. They tested GPX4-inhibiting compounds in drug-treated cancer persister cells, in untreated cancer cells, as well as in normal cells, and found that only drug-treated cancer persister cells were effectively destroyed by GPX4-inhibiting compounds. In detail, GPX4-inhibiting compounds induced ferroptotic cell death in drug-treated cancer persister cells.

The team also carried out experiments in mouse models. The results showed that loss of GPX4 function prevented tumor relapse in vivo. Collectively, these data demonstrate that GPX4 inhibition selectively leads to cell death in cancer persister cells. Therefore, targeting GPX4 represents a potential way to overcome drug resistance and improve cancer treatment.

GPX4 (glutathione peroxidase 4) is an essential antioxidant enzyme, whose activity protects cells against oxidative damage. Previous studies have shown that GPX4 knockout mice die at the embryonic stage and GPX4 loss leads to cell death in various cells. Additionally, it has been established that the ablation of GPX4 could induce ferroptotic cell death.
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