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Researchers at the University of California, San Francisco have discovered a genetic weakness that allows oncologists to eliminate multiple types of cancer. The recent online publication of Nature's findings suggests that if it can be confirmed in human patients, it is possible to find a new way to effectively prevent cancer recurrence.
The new findings of researchers at the San Francisco campus are based on "persister cells" discovered seven years ago.
Oncologists generally believe that drug resistance is the result of the evolution of cancer genes. However, in 2010, researchers at the Massachusetts General Hospital Cancer Center found that escaping cancer treatment may not require new genetic mutations: a small group of cancer cells within the tumor, known as "drug-resistant cells" - at the time of treatment Dormancy allows them to survive and then recover and produce new cancer growth. Non-genetic resistance often occurs in cancer patients, and these naturally highly resistant cells are powerful candidates for explaining this phenomenon.
Looking for cell biology weaknesses in drug-resistant strains
In order to find the biological weakness of drug-resistant cells, Dr. Matthew Hangauer of San Francisco and his colleagues used RNA sequencing to find cells of breast cancer resistant cells that survived 9 days after treatment with the high-dose therapeutic drug lapatinib. Differences in gene activity between treated breast cancer cell lines. They found that drug-resistant cells have higher levels of typical mesenchymal cells (constituting bone, cartilage, muscle, and fat cells), but are not active in cells that are resistant to some of the necessary genes for oxidative stress.
Earlier this year, some co-authors of this article participated in the publication of a Nature, found that mesenchymal cancer cells are prone to oxidoptosis, suggesting that this pathway can block the enzyme valley. Glutathione peroxidase 4 (GPX4) triggers.
Dr. Hangauer said: "Now we connect our findings: drug-resistant cells have strong mesenchymal-like gene expression signatures, which raises questions - whether the viability of drug-resistant cells under cancer treatment depends on whether At Gpx4?"
Gpx4 inhibitory compounds kill resistant cell lines
To date, the team found that Gpx4 inhibitory compounds can selectively kill drug-treated breast cancer-resistant cells in the laboratory without significant effects on untreated breast cancer cells and normal breast cells. The authors then extended this discovery to a variety of different types of cancer, including melanoma, lung cancer, and ovarian cancer. In each case, experiments in tumor cell lines have shown that Gpx4 inhibitor drugs trigger oxidative cell death in treated drug-resistant cell lines, but not in untreated cancer cells.
"We have always assumed that our observations are for breast cancer, but we decided to test other tumor types and are happy to see that this is effective in all tumors. This is a very rare thing," Dr. Hangauer continued: "We also found that it surpassed the specific drugs originally used for anti-cancer, suggesting that this may be a versatile strategy to eliminate the ability of cancer to evade treatment and future recurrence."
To treat drug-resistant cancer in humans, the researchers conducted preclinical tests in laboratory mice. The GPx4 gene in melanoma cells was inactivated using CRISPR-Cas9 gene editing technology. These cells were transplanted into mice to form tumors lacking Gpx4 enzyme, and then treated with melanoma-targeted drugs to reduce tumors. They found that the control tumor quickly relapsed, but the tumor lacking Gpx4 would never be longer.
Therapeutic prospects of Gpx4 inhibitory compounds
These results suggest that the ability of targeted therapy combined with tumors and Gpx4 inhibitors to eliminate cells of resistant strains may be a very promising approach to prevent relapse in a variety of human cancers.
Dr. Hangauer emphasized that the current Gpx4 inhibitory compounds are not able to effectively penetrate tissue and develop new compounds that can be used to kill cells of resistant strains in human cancer patients, which is the focus of future research. Dr. Hangauer emphasized that it is important to completely block Gpx4 in animals. However, a Gpx4 targeted drug can be designed to eliminate resistant cell lines with a local effective dose without damaging other cells in human patients.
Dr. McManus, the author of the article, said: "There are billions of dollars in efforts to produce small molecules that kill specific cancer cells, but the common mistake of these treatments is that even in the most smooth conditions, doctors usually only Say 'relief' because what happens is often a chronic cancer rebound. And this study is to determine a wide range of roles and find unique genetic loopholes in many different cancers, which allows us to eventually eliminate 100% of cancers and prevent recurrence. ""
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