Immune System Attacks Cancer Gene with Drugs

Immune System Attacks Cancer Gene with Drug
Immune System Attacks Cancer Gene with Drug

The human immune system is highly adept at evading tumor cells, which build physical barriers, wear masks, and use molecular cunning to restrain the immune system. Researchers from UC San Francisco have now developed a drug that overcomes some of these barriers and marks cancer cells for the immune system to destroy.

A mutant form of the KRAS protein is pulled to the surface of cancer cells by the new treatment, which when combined with the drug works as an "eat me" flag. The immune system can then be stimulated with an immunotherapy to successfully destroy all cells displaying this flag.

“The immune system already has the ability to identify mutant KRAS, but it often has trouble doing so. Adding this identifier to the protein greatly aids the immune system,” said Kevan Shokat, a chemist at UCSF and a Howard Hughes Medical Institute researcher who helped lead the new research.

KRAS mutations are one of the most common gene mutations in cancer and are found in approximately 25% of malignancies. Sotorasib, which the Food and Drug Administration (FDA) has provisionally approved for use in the treatment of lung cancer, also targets mutated KRAS, and it is possible that these two treatments will eventually work well together.

"It's interesting to have a new technique that uses 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. As a result, we believe that cancer patients can get deeper and longer responses.

Foreign cells are often identified by the immune system, thanks to the peculiar proteins emanating from their surfaces. However, there are not many distinguishing proteins on the outer surface of cancer cells. Instead, most of the proteins that distinguish tumor cells from normal cells are found inside cells, out of reach of the immune system.

Although KRAS is frequently found in tumors, it was long thought to be insurmountable. The mutant form of KRAS, which promotes tumor cell growth and functions inside cells, usually differs from normal KRAS with only one minor change and lacks a distinct drug binding site. However, Shokat has done extensive research on the protein in recent years and has found a druggable domain in mutant KRAS. His work helped create and approve sotorasib.

However, not all KRAS mutant patients benefit from sotorasib, and some of the tumors it shrinks develop resistance and recur. Shokat, Craik and colleagues questioned whether there is another strategy to inhibit KRAS.

The team's latest research shows that ARS1620, a targeted KRAS drug comparable to sotorasib, binds to mutant KRAS and does more than prevent KRAS from affecting tumor growth. It also causes the cell to identify the ARS1620-KRAS complex as a foreign substance.

Because it's so similar to the healthy protein, "this mutant protein often floats under the radar," Craik says. But as soon as you attach this drug to it, it appears immediately.

This shows that the protein is processed by the cell and transported to its surface as a warning to the immune system. KRAS, once hidden inside, is now visible on the outer surface of tumor cells like an "eat me" flag.

The UCSF team then scanned a library of billions of human antibodies to find those that could recognize this KRAS flag as a result of mutant KRAS moving from inside the cells to the outside. The most promising antibody found by the researchers was able to bind tightly to both the ARS1620 drug and the ARS1620-KRAS complex, as demonstrated by studies on both isolated protein and human cells.

The team then developed an immunotherapy that focused on this antibody, encouraging the immune system's T cells to detect the KRAS flag and select cells for eradication.

They discovered that tumor cells with the mutant KRAS gene and those treated with ARS1620, including those who had previously developed resistance to ARS1620, could be destroyed by the new immunotherapy.

According to Shokat, "What we're showing here is proof of principle that a cell resistant to currently available drugs can be killed with our technique."

Further testing in both humans and animals is needed before the treatment can be applied in clinical settings.

According to the researchers, the new strategy could open the door to comparable additional combinations of targeted drugs and immunotherapies, as well as combination therapy for malignancies with KRAS mutations.

Craik claims this technology is a platform. “We want to pursue additional targets that could similarly deliver compounds to the cell surface and make them immunotherapy-friendly.”

Craik claims this technology is a platform. “We want to pursue additional targets that could similarly bring compounds to the cell surface and make them immunotherapy-friendly.”

: Source: medicalxpress

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