One of the reasons why it is so difficult to eliminate cancer is because it is able to evade the immune system action. Precisely, a good part of the recent research in cancer therapies focuses on finding ways to leave tumors without this ability.

The immune system as a weapon

Now, a team of researchers from the San Francisco California Unit has developed a drug that overcomes some of these barriers and ‘marks’ cancer cells to be destroyed by the immune system.

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This new therapy, they explain in an article published in the scientific journal Cell Cancerdrives a mutated version of the KRAS protein to the surface of cancer cells, where acts like a target. Subsequently, an immunotherapy stimulates the immune system so that it effectively eliminates all the cells that carry this signal.

The system is based on the fact that mutations of the KRAS protein are present in 25% of all tumors, making them one of the most common genetic mutations in cancer. Furthermore, KRAS mutations are already the target of the drug sotorasib, which has been preliminarily approved for use in lung cancer, so it is possible to combine both strategies.

Mutated proteins as targets

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Normally, the immune system recognizes foreign cells by the unusual proteins that they present on their surfaces. This is much more difficult to achieve with cancer cells, for which there are few unique proteins on the outside. Instead, most of the proteins that differentiate tumor cells from healthy cells are found inside them, where they are not detectable by the immune system.

For this same reason, it is also particularly difficult to develop drugs whose target is these proteins. Sotorasib is an example of success, since binds to mutated versions of the KRAS proteinbut it does not work in all patients and many tumors also end up developing resistance to the drug.

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In contrast, the drug used by these authors, ARS1620, not only binds to the mutated KRAS protein but also alerts the cell that contains it, which recognizes the ARS1620-KRAS complex as a foreign molecule and drives it towards its surface. This, in turn, ‘calls the attention’ of the immune system.

Combined therapies

The process does not end there. The team of researchers, thanks to achieving bring out mutated KRAS proteins, was able to scan a library of billions of human antibodies to identify those that recognize the KRAS target. One of these antibodies was capable of strongly binding the ARS1620 drug and the ARS1620-KRAS complex.

To use this antibody, it was necessary develop an immunotherapy around it, to specifically attack those cells with the KRAS mutation and that had been treated with ARS1620, including those that had already generated resistance to the latter drug.

The results obtained so far are promising, but the truth is that there are still it will be necessary to replicate them in animal models and later in humans before being able to use this strategy clinically. What the authors emphasize, however, is that these same principles can be used to test not only combination treatments in cancer cells with KRAS mutations, but also combinations of other treatments with immunotherapies.

References

Ziyang Zhang, Peter J. Rohweder, Chayanid Ongpipattanakul, Koli Basu, Markus Frederik Bohn, Eli J. Dugan, Veronica Steri, Bryon Hann, Kevan M. Shokat, Charles S. Craik. A covalent inhibitor if K-Ras(G12C) induces MHC class I presentation of haptenated peptide neoepitopes targetable by immunotherapy. Cancer Cell (2022), DOI: https://doi.org/10.1016/j.ccell.2022.07.005