“Cells are becoming more aggressive”: Russian scientists have discovered the reasons for the ineffectiveness of anti-cancer therapy

Russian biochemists have determined which change in the DNA of cancer cells makes them resistant to one type of therapy, namely treatment with MDM2 protein inhibitors. This protein blocks the natural processes of cell death with genetic damage. Medicines can solve this problem by restoring the body's natural mechanisms of fighting cancer. However, in some cases, such drugs quickly lose their effectiveness and the tumor continues to grow. The authors of the work have found the molecular causes of this resistance and found ways to combat it.

Russian scientists from the Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences and Lomonosov Moscow State University have found out which mutation in cancer cells makes them resistant to a certain type of therapy. Such therapy should normally suppress the work of a special protein that blocks the natural mechanisms of self-destruction of cancer cells, but tumors often develop resistance to it. The authors of the study also selected a combination of drugs that can overcome the resistance of cancer cells. The work was supported by the Russian Science Foundation. The results were published in the journal Apoptosis. This was reported to RT by the press service of the RSF.

Normally, the p53 protein protects the body from developing malignant tumors. This protein provokes apoptosis (self-destruction) of cells with damaged DNA, i.e. potentially malignant cells. That is why the p53 protein is often called the “guardian of the genome.”

However, another protein, MDM2, can disrupt the work of this protective mechanism. It blocks the work of p53, as a result of which cancer cells can begin to divide uncontrollably and form a tumor. It has been established that MDM2 is found in large quantities in cancerous formations, so today the analysis of this protein is often used to diagnose various oncological diseases.

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Currently, drugs whose mechanism of action is aimed at suppressing MDM2 are being studied in detail. The problem is that over time, tumor cells begin to adapt to drugs, significantly reducing the effectiveness of therapy. The reasons and mechanisms of cancer cell adaptation have remained largely unknown until recently.

To find out, the study's authors used various cell lines of neuroblastoma, a tumor of the nervous tissue that often occurs in children, available in the laboratory.

The cell culture was treated with drugs that suppressed the MDM2 protein until only cells resistant to this effect remained in the culture dishes. After examining them and comparing them with the original material, the scientists found that drug resistance was caused by a single mutation in the gene encoding the p53 protein. This leads to the replacement of one amino acid in the protein molecule, and it is no longer able to perform its protective functions.

During the experiments, it was discovered that neuroblastoma cells with such a mutation of the p53 gene begin to divide faster, and the tumor quickly develops the ability to metastasize.

“It is important to note that p53 is one of the most frequently mutated proteins in the human body. Thus, approximately 50% of tumor development cases are accompanied by mutations in p53. Moreover, tumors containing mutant p53 can become more malignant,” Nikolai Pervushin, a research fellow at the Lomonosov Moscow State University Laboratory for the Study of Apoptosis Mechanisms, told RT.

The resistance of cells with the p53 mutation to therapy can be overcome by correctly combining drugs with different mechanisms of action, the authors of the study also found. Thus, it was experimentally established that the viability of cancer cells decreases if they are exposed to drugs that suppress the MDM2 protein and BH3 mimetics, substances that trigger programmed cell death through other molecular pathways.

“Since mutations in the p53 protein make cancer cells more aggressive, such changes in the genome sequence can serve as a potential biomarker of an unfavorable prognosis for patient treatment. Therefore, when using MDM2 inhibitors in clinical practice, it is necessary to take into account that mutations may appear in the p53 protein that negatively affect the effectiveness of the drugs,” Gelina Kopeina, Doctor of Biological Sciences and head of the Laboratory of Cell Death Mechanisms at the Institute of Molecular Biology of the Russian Academy of Sciences, told RT.