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Cancer cells withstand chemotherapy without unnecessary mutations

Kirill Stasevich, Science and Life (nkj.ru )

Chemotherapy does not always get rid of cancer completely. Often, after treatment, the tumor occurs again, and the reason for this is individual cells that have proved resistant to drugs. There are not so many of them, and most of them, although they managed to survive the "chemical attack", can no longer share.

However, some resistant (or persistent) cells manage to re–enter the cell cycle - or, more simply, begin to divide, forming a new tumor. It can be assumed that such cells at one time had special mutations that allowed them to survive. However, recently there is more and more evidence that the mechanisms of resistance can be not only genetic, but also extragenetic – that is, cells manage to survive without mutations, without changes in the genetic text.

One of such works (Oren Y, et al. Cycling cancer persistent cells arise from lineage with distinct programs) was recently published in Nature by The Broad Institute at the Massachusetts Institute of Technology. They experimented with lung cancer cells that had become malignant due to a mutation in the epidermal growth factor (EGFR) gene.

If you block the EGFR protein with a substance called osimertinib, the cells will stop dividing and begin to die. But if most of the different cell lines (and all the lines were related to lung cancer with a mutation in EGFR) died from the drug, then in 8% resistant cells appeared, and in 13% of these eight resistant cells were also capable of division. In other words, resistant cells appear quite early and from special cell lines (or, roughly speaking, groups) inside the tumor.

Such cells were relieved of the drug for a while, and then they were treated again with a poisonous therapeutic molecule. As it turned out, they became sensitive to treatment again. If they owed their resistance to the drug to a mutation, then the mutation would surely work again – the cells would become resistant once and for all. Hence, the researchers concluded that the mechanism of resistance to therapy is not associated with changes in DNA.

It was possible to understand what this mechanism is with the help of sophisticated methods that allow analyzing the activity of genes in a single cell. It turned out that resistant cells dramatically increased antioxidant protection. When treated with osimertinib, there are many reactive oxygen species in cells – oxygen radicals, aggressive oxidants that spoil cellular biomolecules. And the more active the antioxidant systems are, the more chances a cell has to survive, and not just survive, but also continue to divide: in resistant cells that stopped dividing, the defense systems worked weaker than those who not only withstood the drug attack, but were able to continue to multiply later.

One of the main antioxidant genes turned out to be NRF2 – if the activity of NRF2 was artificially increased in one or another line of cancer cells, then more resistant cells appeared. In addition, resistant cells had more oxidized fatty acids. (Probably, cells fight oxidative stress by quenching it with the help of fatty acids and thereby protecting against damage, for example, DNA). It can be assumed that drugs that suppress the activity of NRF2 or prevent the oxidation of fatty acids will help to cope with cancer cells resistant to chemotherapy, and cancer cells from different tumors.

Although different types of cancer can occur due to different mutations, and drugs against them are also used differently, the authors of the work were able to show that resistance to therapy in melanoma cells, breast cancer and colorectal cancer depends on the activity of NRF2 and the degree of oxidation of fatty acids. Similar results were obtained not only in experiments on cell cultures, but also in experiments with mice in which a tumor with a mutation in the EGFR gene, similar to human, was formed in the lungs.

Once again, we recall that the strengthening of antioxidant protection occurred without special mutations. Genes are able to work stronger or weaker without changes in the DNA that encodes them, and in some cancer cells, protective genes worked more actively due to some random factors.

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