Unraveling cancer's resistance to chemotherapy
How to recognize the cause of drug resistance of a cancerous tumor
And even if we know the main mutation that caused cancer, this is not enough: tumor cells still find a way to bypass treatment, although we would seem to have blocked the mechanism of action of this mutation...
One of the most obvious examples in this sense is melanoma. In half of the cases, this cancer appears due to a mutation in the BRAF gene, which regulates cell division. There are drugs that suppress the effect of this particular mutation on the molecular signals responsible for cell reproduction. And indeed, with such therapy, melanoma disappears – but only for nine months. Obviously, cancer cells bypass treatment with the help of some other genes, and researchers from the Broad Institute and the Dana-Farber Institute (both in the USA) tried to find out who helps them.
Dividing human melanoma cells (photo by wellcome images).To do this, Cory Johannessen and his colleagues took turns stimulating the activity of 15,000 genes in melanoma cells with a mutation in BRAF.
For comparison, it is worth mentioning that the entire human genome includes 20 thousand genes. Each time, by increasing the activity of a particular gene, tumor cells were treated with conventional drugs – and by the way they reacted to them, it was possible to tell whether a particular gene was helping to acquire resistance.
As a result, as the researchers write in Nature (A melanocyte lineage program conferences resistance to MAP kinase pathway inhibition), they managed to understand how melanoma cells "bypass" chemotherapy. Scientists have identified signaling pathways that the cell could use to counteract drugs, and the fact that such an impressive mass of genes was analyzed in this way allows us to hope that science now has all possible mechanisms for such resistance. The results of the gene search were also confirmed on several lines of melanoma cells, which, in addition to BRAF mutations, carried several other genetic damages.
At the same time, as probably should be expected, drug resistance in tumor cells arises in connection with a fairly specific range of genes that normally control the development and growth of skin cells. When a mutation damages BRAF, the cells that were intended to turn into melanocytes do not turn into them, but begin to divide uncontrollably. This is due to the fact that transcription factors (proteins necessary for the synthesis of RNA on DNA and for the regulation of this synthesis) are activated in such mutant cells, on which division depends. Modern medicines are aimed not at these factors themselves, but at the chains of molecular signals that lead to them. After the cancer molecular signals have stopped coming to the transcription factors, the cell has a chance to return to the normal path of transformation into a normal melanocyte.
However, as the researchers found out, this normal pathway of development at some point includes the same "cancerous" transcription factors that were previously triggered by oncogenic mutation. As a result, a healthy cell is filled with proteins that turn it into a tumor. So, in the end, transcription factors are to blame for the appearance of drug resistance, which, for some unknown reason, begin to work the wrong way.
These methods are currently only being tested in clinical trials, but if they justify themselves, then, together with conventional methods of treatment aimed at neutralizing the BRAF mutation, they can reduce the likelihood of tumor recurrence to zero.
Transcription factors are never used as a target for drug molecules: they are vital for the cell, and in this case there is a risk of destroying everything in the body in general. However, according to the authors of the work, they can be calmed down if they act on chromatin, that is, on the mechanics of DNA stacking in the chromosome. If you act on proteins that affect the density of DNA stacking, its availability for transcription, then through them you can neutralize the unnecessary activity of transcription factors.
However, in the context of the work under consideration, this is in particular, the main thing is the method that allowed a systematic search for the causes of tumor resistance to drugs among thousands of genes. Although the authors dealt with only one type of cancer, nothing prevents them from applying their technology of massive molecular genetic search to other types of tumors.
Prepared based on the materials of the Broad Institute: Predicting cancer's next move.
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