Cancer drugs hit wrong targets

September 17, 2019  10:48

Experimental cancer drugs do not work as they appear to their developers. Cancer cells differ from healthy ones by their molecular genetic portrait: some genes in cancer cells work especially hard, and therefore they have especially many proteins, which should normally be few. These genes and these proteins provide malignant cells with their malignancy, and if we suppress the work of any such protein - for example, create a molecule that will prevent it from interacting with other proteins - this will damage the cancer cell itself. It will stop sharing or die at all, and the disease will come to naught.

However, there is a risk of overshooting and choosing the wrong target for the drug, said researchers from the Laboratory at Cold Spring Harbor in an article published in Science Translational Medicine.

They searched for genes whose activity in cancer cells could indicate a poor clinical prognosis. But in order to find a new ‘cancerous’ gene, it needs to be compared with the old one, that is, with the one about which it is well known that malignant cells need it, Science and Life reported.

The gene encoding the MELK protein was chosen as such a reliable old gene - cancer cells synthesize it a lot and in various scientific papers it has been argued that MELK is very important for tumors. But when the MELK gene was turned off using genetic editing, the cancer cells hardly felt it. And if they wanted to create a medicine that would hit MELK, then the medicine would hardly be effective.

Then it was decided to test the ten latest drugs that were created in order to block the effect of ‘cancerous’ proteins, and which had already been tested in clinical trials involving about 1000 people; the target proteins against which these drugs were created are devoted to more than 180 scientific publications. The experimental drugs acted on cancer cells, but they didn’t act as their developers had suggested. Those target proteins against which they were created were not so important for cancer cells. But the anticancer effect that could be observed was a side effect of the fact that the drugs acted on some other molecules.

The reason for this inaccuracy, according to the authors of the work, was the peculiarities of the methods by which suitable target proteins are sought. In order to understand how a cell will react if a protein stops working, so-called interfering RNAs, small ribonucleic acid molecules that turn off the synthesis of a particular protein, are launched into it.

The problem with this method is that interfering RNAs can affect the synthesis of some other proteins. If the CRISPR genetic editing method is used, then you can disable only the gene that you need, and no other. There are also questions regarding the accuracy of the CRISPR method, but compared to interfering RNAs, it really works much more specifically.

Finding out the true mechanisms of action of experimental anticancer drugs, researchers using CRISPR turned off the targets against which the drugs were created. Cancer cells, like the MELK protein case described above, survived. But besides, if such cells, devoid of the target for this or that medicine, were given this same drug, then he killed the cells - although, we repeat, his target was not in it. That is, there was some kind of collateral secret target through which the medicine still acted.

In one case, researchers even managed to find such a secret target - because of the ability of cancer cells to become resistant to drugs. The cells were treated with a very, very large amount of one of the experimental drugs, so that only those that acquired a mutation of resistance survived among the cells. This mutation turned out to be not in the gene that encoded the putative target protein, but in a completely different one. And then, when a mutation was introduced into the detected side target that made the protein insensitive to the drug, then the cells with this mutation survived despite the drug - because the real target was removed from the attack.

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