Tumor cells are notoriously good at evading the human immune system; they put up physical partitions, wear disguises and handcuff the immune system with molecular tricks. Now, UC San Francisco researchers have developed a drug that overcomes a few of these barriers, marking cancer cells for destruction by the immune system.

The brand new therapy, described Sept. 12 in Cell Cancer, pulls a mutated version of the protein KRAS to the surface of cancer cells, where the drug-KRAS complex acts as an “eat me” flag. Then, an immunotherapy can coax the immune system to effectively eliminate all cells bearing this flag.

“The immune system already has the potential to acknowledge mutated KRAS, however it normally cannot find it thoroughly. Once we put this marker on the protein, it becomes much easier for the immune system,” said UCSF chemist and Howard Hughes Medical Institute Investigator Kevan Shokat, PhD, who helped lead the brand new work.

KRAS mutations are present in about one quarter of all tumors, making them one of the vital common gene mutations in cancer. Mutated KRAS can be the goal of sotorasib, which the Food and Drug Administration (FDA) has given preliminary approval to be used in lung cancer, and the 2 approaches may eventually work well together.

It’s exciting to have a latest strategy leveraging the immune system that we are able to mix with targeted KRAS drugs. We suspect that this may lead to deeper and longer responses for cancer patients.”

Charles Craik, PhD, lead study writer and professor of pharmaceutical chemistry, UCSF

Turning cancer markers inside out

The immune system typically recognizes foreign cells because of surprising proteins that jut out of their surfaces. But in relation to cancer cells, there are few unique proteins found on their outsides. As a substitute, most proteins that differentiate tumor cells from healthy cells are contained in the cells, where the immune system cannot detect them.

For a few years, KRAS-;despite how common it’s in cancers-;was considered undruggable. The mutated version of KRAS, which drives the expansion of tumor cells, operates inside cells. It often has just one small change that differentiates it from normal KRAS and doesn’t have a readily visible spot on its structure for a drug to bind. But over recent many years, Shokat carried out detailed analyses of the protein and discovered a hidden pocket in mutated KRAS that a drug could block. His work contributed to the event and approval of sotorasib.

Sotorasib, nevertheless, doesn’t help all patients with KRAS mutations, and among the tumors it does shrink grow to be resistant and begin growing again. Shokat, Craik and their colleagues wondered whether there was one other technique to goal KRAS.

In the brand new work, the team shows that when ARS1620-;a targeted KRAS drug much like sotorasib-;binds to mutated KRAS, it doesn’t just block KRAS from effecting tumor growth. It also coaxes the cell to acknowledge the ARS1620-KRAS complex as a foreign molecule.

“This mutated protein is often flying under the radar since it’s so much like the healthy protein,” says Craik. “But once you attach this drug to it, it gets spotted instantly.”

Meaning the cell processes the protein and moves it to its surface, as a signal to the immune system. The KRAS that was once hidden inside is now displayed as an “eat me” flag on the surface of the tumor cells.

A promising immunotherapy

With the shift of mutated KRAS from the within to the surface of cells, the UCSF team was next in a position to screen a library of billions of human antibodies to discover those that would now recognize this KRAS flag. The researchers showed with studies on each isolated protein and human cells that essentially the most promising antibody they’d identified could bind tightly to the drug ARS1620 in addition to the ARS1620-KRAS complex.

Then, the group engineered an immunotherapy around that antibody, coaxing the immune system’s T cells to acknowledge the KRAS flag and goal cells for destruction. They found that the brand new immunotherapy could kill tumor cells that had the mutated KRAS and were treated with ARS1620, including people who had already developed resistance to ARS1620.

“What we have shown here is proof of principle that a cell proof against current drugs could be killed by our strategy,” says Shokat.

More work is required in animals and humans before the treatment might be used clinically.

The researchers say that the brand new approach could pave the best way not just for combination treatments in cancers with KRAS mutations, but additionally other similar pairings of targeted drugs with immunotherapies.

“It is a platform technology,” says Craik. “We might prefer to go after other targets that may additionally move molecules to the cell surface and make them amenable to immunotherapy.”

Source:

University of California – San Francisco

Journal reference:

Zhang, Z., et al. (2022) A covalent inhibitor of K-Ras(G12C) induces MHC class I presentation of haptenated peptide neoepitopes targetable by immunotherapy. Cancer Cell. doi.org/10.1016/j.ccell.2022.07.005.