Cancer cells are very effective at hiding their true nature from the immune system and this prevents them from being discovered and destroyed by our defenses and can continue to multiply uncontrollably and spread to other areas of the body from the original tumor, which is known as metastases.
Mutations in the KRAS gene proteins are present in up to one in four cancers and therefore KRAS-targeted treatments have been created, but there are still tumors resistant to these therapies. Now, scientists at the University of California San Francisco (UCSF) have developed a new drug that marks cancer cells so that the immune system can identify them.
Specifically, the new therapy that these researchers have created attracts a mutated version of the KRAS protein to the surface of tumor cells, where the drug-KRAS complex acts as a flag indicating “eat me”. An immunotherapy can then induce the immune system to effectively kill all cells that have this flag.
“It’s exciting to have a new strategy that harnesses the immune system and we can combine with targeted KRAS drugs, this could lead to deeper and longer responses for cancer patients.”
Like in the movie Invasion of the Ultrabodies (1978), in which the aliens who had taken possession of a human body pointed their index fingers at the people who had been spared so far so that they too would be abducted by their fellow human beings In a similar way, the new drug works by signaling cancer cells so that the immune system recognizes them as the target to be eliminated.
“The immune system already has the potential to recognize mutated KRAS, but it usually can’t find it very well. When we put this marker on the protein, it becomes much easier for the immune system,” said Kevan Shokat, a UCSF chemist and Howard Hughes Medical Institute investigator who helped lead the new work, the results of which have been published. in CancerCell.
The mutated KRAS is also the target of the drug sotorasib (Lumykras®), which received preliminary approval from the United States Food and Drug Administration (FDA) for the treatment of lung cancer, and whose marketing was also authorized by the Commission Commission in 2021 for the treatment of adults with advanced non-small cell lung cancer (NSCLC) with the KRASG12C mutation.
According to the study authors, both approaches could work well in combination. “It’s exciting to have a new strategy that harnesses the immune system that we can combine with targeted KRAS drugs,” said Charles Craik, lead author of the study and professor of pharmaceutical chemistry at UCSF. “We suspect this could lead to deeper and longer responses for cancer patients.”
Unmasking cancer cells to make them vulnerable
Our immune system is primed to recognize foreign agents because they have unusual proteins on their surface, but in the case of cancer cells, there are few unique proteins present on their exterior, while most of the proteins that differentiate tumor cells from healthy ones are inside, where the immune system cannot detect them.
Although KRAS mutations are one of the most frequent genetic mutations in cancers, for a long time it was not considered that they could be a target for the treatment of this disease. The mutated version of KRAS that enhances cancer cell growth acts inside the cells, usually there is only a small change that differentiates it from normal KRAS, and there is also no easy-to-locate point in its structure where it can attach the drug. But in recent decades, Shokat has performed detailed analyzes of the protein and discovered a hidden pocket in mutated KRAS that a drug could block. His work contributed to the development and approval of sotorasib.
However, sotorasib is not effective in all patients with KRAS mutations, and some of the tumors it shrinks become resistant to treatment and grow back. Therefore, Shokat, Craik and their colleagues decided to look for another alternative targeting KRAS.
New immunotherapy could kill cancer cells that had mutated KRAS and were treated with ARS1620
In the new research they have shown that when ARS1620 – a KRAS-targeting drug similar to sotorasib – binds to mutated KRAS, it not only prevents KRAS from driving tumor growth, but also induces the cell to recognize the ARS1620-KRAS complex as a foreign molecule.
“This mutated protein usually goes unnoticed because it’s so similar to the healthy protein,” explains Craik, “but when you add this drug to it, it’s spotted right away.” In this way, the cell processes the protein and moves it to its surface, as a signal to the immune system. Thus, the KRAS that had been hidden inside shows up as an “eat me” flag on the outside of the tumor cells.
An effective immunotherapy against treatment-resistant tumors
Following the shift of mutated KRAS from the inside to the outside of cells, the UCSF group screened a library of billions of human antibodies to identify those that could now recognize this KRAS flag. They conducted studies on both isolated proteins and human cells that showed that the most promising antibody identified was capable of tightly binding the drug ARS1620 as well as the ARS1620-KRAS complex.
They then designed an immunotherapy around that antibody, inducing the immune system’s T cells to recognize the KRAS flag and target cells for destruction. They found that the new immunotherapy could kill cancer cells that had mutated KRAS and were treated with ARS1620, including those that had already developed resistance to ARS1620.
“What we have shown here is proof of principle that our strategy can eliminate a cell that is resistant to current drugs,” says Shokat. Although further studies in animals and people are necessary before the treatment they have developed can be used in clinical practice, the researchers assure that this new therapeutic approach could serve as a basis for both combined treatments in cancers with KRAS mutations, as well as for other similar combinations of targeted drugs with immunotherapies.
“This is a platform technology,” Craik concludes. “We would like to look for other targets that can also move molecules to the cell surface and make them amenable to immunotherapy.”
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