Tumor cells are very good at evading the body’s immune system, which is the main reason why cancer is so difficult to fight. But recently, a UC San Francisco research team has developed a new therapy that can mark cancer cells with KRAS mutations so that the immune system can better recognize them, which could become a powerful tool to help immunotherapy fight cancer.
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Flagging KRAS mutant cancer cells
The immune system can distinguish foreign cells from different proteins on the cell surface, but it cannot do this for cancer cells, mainly because from the outside, cancer cells have few unique proteins to identify, and the most of them are differentiated from healthy cells proteins are all located inside cells, and the immune system cannot go deep enough to detect them.
Among them are KRAS mutations that drive the growth of tumor cells. Although KRAS mutations are present in about a quarter of tumors and are considered one of the most common genetic mutations in cancer, they were considered undruggable for many years because they are located inside tumors.
After nearly ten years of continuous detailed analysis of KRAS proteins, the situation has gradually changed. For example, the targeted drug Sotorasib (AMG510) for KRAS G12C has entered clinical trials, but no but Sotorasib is currently used for non-small cell lung cancer. NSCLC), cannot help all cancer patients with KRAS mutations, and also has drug resistance issues. To this end, the research team set out to explore whether there was another way to target KRAS.
In the new “Cancer Cell” study, the research team showed a similar and equally targeted drug to Sotorasib KRAS G12C The mutated drug ARS1620, when bound to mutated KRAS, not only blocks KRAS from affecting tumor growth, but also induces cells to treat the bound ARS1620-KRAS complex as a foreign molecule, allowing cells process the protein and move it to the surface, while This is equivalent to giving cancer cells an “eat me” signal, making it easier for immune cells to detect.
After that, the research team went deeper into the multi-billion human antibody library, and screened for antibodies that could recognize this “eat me” signal. Research on isolated proteins and human cells showed that the most antibodies could be combined promising that the team was discovered. with drugs ARS1620 and the ARS1620-KRAS complex bind tightly.
Also effective against tumor cells that have developed drug resistance
The research team then designed an immunotherapy around the antibody, tricking T cells into recognizing the mutational hallmark of KRAS and targeting it for destruction. The results showed that the new therapy could kill not only tumor cells with KRAS mutations and treated with ARS1620, but even those that had become resistant to ARS1620.
More research must be done in animals and humans before it goes into clinical trials. But the researchers are optimistic about the future, believing that the new therapy could not only help treat cancers with KRAS mutations, but also pave the way for other similarly targeted drugs to be paired with immunotherapies.
The study’s lead author, Charles Craik, Ph.D., professor of medicinal chemistry, said the discovery of a new strategy to harness the immune system in conjunction with drugs targeting KRAS is exciting, and the team expects that this leads to deeper and longer. lasting immune responses in cancer patients. “This is a platform technology, and we want to look for other targets that could also move molecules to the cell surface and make them suitable for immunotherapy.”
Further reading: Simulating the crawling power of immune cells, a new method can discover candidate antigens for immunotherapy faster and more accurately!
Addresses:
1. Cancer Cell, 2022, https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00318-X
2. https://www.ucsf.edu/news/2022/09/423661/drug-turns-cancer-gene-eat-me-flag-immune-system
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