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DNA in human cells is constantly exposed to damage caused by normal cell metabolism. However, healthy cells are able to repair this damage.
Repairs often use BRCA1 and BRCA2 proteins. However, if these are defective, there are more mutations in the DNA and this can lead to cancer. According to a report from the University of Bern, the development of bad and ovarian cancer is badociated with lesions of these two restorative proteins.
Tumors with such a defect can be treated with a new therapy called Parp. Inhibitors are fought. If the protein complex, which is also involved in DNA repair, is blocked in addition to the defective repair proteins, the cancer cells die. Healthy body cells, whose repair proteins work, survive on the other hand. Unfortunately, patients often develop resistance to PAR inhibitors.
A research team under the direction of the University of Bern and the Netherlands Cancer Research Center (NKI) has developed three different resistance mechanisms in collaboration with British, Danish, Canadian and Swedish scientists. Parp inhibitors identified. To this end, researchers used the so-called Crispr / Cas9 gene scissors to study which genes control cell repair in relation to cancer treatment. They stopped certain genes in a targeted way.
They genetically modified millions of BRCA mutant cancer cells. After these millions of cells were treated with Parp inhibitors, these cells became resistant because of some genetic changes and survived the treatment.
"The changes in these cells gave us an indication of the genes involved in the development of resistance.Sven Rottenberg is quoted in the communication of the Vetsuisse Faculty of the University of Bern. have also grown tumor cells in a three-dimensional matrix.This has the advantage that these cell cultures are closer to real tumors.
Using these tests, scientists have discovered that the success of Inhibitors depended on the function of other proteins involved in the repair of DNA breaks.If the function of these partially discovered proteins fails, this leads to resistance to parp inhibitors. the "Cancer Cell", "Cell Reports" and "Nature" journals reported their results.
Results need to be incorporated into new approaches to resistance In our models, we have seen that tumors that are resistant to treatment with Parp inhibitors – due to the failure of other DNA repair proteins – can be controlled by radiotherapy or other drugs. already established anticancer drugs such as temozolamide ".
The research was supported by the Swiss National Science Foundation (SNSF), the Swiss Cancer League, the Dutch League Against Cancer (KWF) and the EU (European Research Council, ERC) . In a next step, researchers are now working to find other weak spots of resistant tumors. (SDA)
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