Drug turns cancer gene into ‘eat me’ flag for immune system

  • The ability of tumor cells to evade the immune system is well-known. They put up physical barriers, disguise themselves and trick the immune system with molecular tricks. Researchers at UC San Francisco have now developed a drug to overcome some of these obstacles, marking cancer cells as being destroyed by the immune system.

    The new therapy is described in Cell. It involves bringing a modified version of the protein KRAS onto the surface of cells. This drug-KRAS complex acts like an “eat me!” flag. An immunotherapy treatment can then be used to coax the immune systems to eliminate all cancer cells that bear this flag.

    The immune system has the potential to recognize KRAS mutations, but it isn’t always able to do so well. Kevan Shokat (UCSF chemist, Howard Hughes Medical Institute Investigator), who led the new research, said that the immune system will find it much easier if we place this marker on the protein.

    KRAS mutations can be found in approximately 25% of all cancerous tumors. This makes them one of the most prevalent gene mutations in cancer. Mutated KRAS is also a target of sotorasib. The Food and Drug Administration (FDA), has approved preliminary use for lung cancer treatment.

    Charles Craik Ph.D., a leading study author and professor in pharmaceutical chemistry at UCSF, stated, “It’s exciting that we have a new strategy leveraging immune system, which we can combine with targeted KRAS medicines,” We believe this will lead to longer and deeper responses for patients with cancer.

    Cancer markers inside out

    Because of the unusual proteins found on foreign cells’ surfaces, the immune system is able to recognize them. There are very few proteins that can be found on cancer cells’ outsides. Most proteins that distinguish tumor cells from healthy cells instead are found inside the cells. The immune system is unable to detect them.

    KRAS, despite its prevalence in cancers, was considered untroubled for many years. KRAS mutated, which is responsible for the growth of cancer cells, works inside cells. It often only has one small change that distinguishes it from normal KRAS and doesn’t have a spot in its structure where a drug could bind. Shokat, who has been studying the protein for decades, discovered a hidden pocket within mutated KRAS that could be blocked by a drug. His contributions were instrumental in the approval and development of sotorasib.

    However, Sotorasib doesn’t work for all KRAS mutations. Some tumors that shrink with Sotorasib become resistant to it and grow again. Shokat, Craik, and their coworkers wondered if there was another way of targeting KRAS.

    The team’s new research shows that ARS1620, a targeted KRAS drug like sotorasib, binds to mutated KRAS. It doesn’t just stop KRAS from causing tumor growth. It coaxes cells to recognize the ARS1620KRAS complex and as a foreign molecule.

    Craik says that “this mutated protein is often flying under the radar” because it is so similar to healthy protein. It is easy to spot if you add this drug to it.

    This means that the cell processes the protein, and then moves it to its surface as a signal for the immune system. The KRAS, which was once hidden within the cells, is now visible as an “eat me!” flag outside the tumor cells.

    Promising immunotherapy

    The UCSF team was able to screen a large number of human antibody in order to find those that could recognize the KRAS flag. With both human cells and isolated protein, the researchers demonstrated that the most promising antibody could bind to the drug ARS1620.

    The group then developed an immunotherapy based on that antibody. This allowed the immune systems’s T cells, which recognize KRAS flags and targets cells for destruction, to be coaxed. The new immunotherapy was effective in killing tumor cells with the mutated KRAS. It can also be used to treat those already resistant to ARS1620.

    Shokat says, “What we have shown here is proof that a cell resistive to current drugs can still be killed using our strategy.”

    Before the treatment can be clinically used, more research is required in both animals and humans.

    Researchers believe that this new approach may open the door to combination therapies in cancers with KRAS mutations as well as other similar pairings of targeted medicines with immunotherapies.

    Craik says, “This platform technology is.” “We would like to pursue other targets that could also move molecules to cells surface and make them more susceptible to immunotherapy.”

    The paper was co-authored by Shokat and Craik as well as Peter J. Rohweder and Chayanid Ogpipattanakul, Koli Baseu, Markus F. Bohn and Eli J. Dugan. Byron Hann from UCSF was also a part of the paper.

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