Cancer cells are notorious for being good at evading the human immune system. They put up physical walls, wear disguise and restrict the immune system with molecular tricks. Now, UCSF researchers have developed a drug that overcomes some of these barriers, tagging cancer cells for destruction by the immune system.
“The immune system really does have the ability to recognize mutant KRAS, but it usually doesn’t find it well,” said a chemist at UCSF and Howard Hughes Medical. “When we put that label on the protein, it becomes much easier for the immune system.” Institute researcher Kevan Shokat, Ph.D., who helped lead the new work.
KRAS mutations are found in about a quarter of all tumors, making it one of the most common genetic mutations in cancer. The mutant KRAS is also a target of sotorasib, which the Food and Drug Administration (FDA) has given initial approval for use in lung cancer, and the two approaches may eventually work well together.
“It’s exciting to have a new strategy that takes advantage of the immune system that we can combine with targeted KRAS drugs,” said Charles Crick, PhD, lead study author and professor of pharmaceutical chemistry at UCSF. “We suspect this may lead to deeper and longer responses in cancer patients.”
Turning signs of cancer from the inside out
The immune system usually recognizes foreign cells because of the unusual proteins that protrude from their surfaces. But when it comes to cancer cells, there are a few unique proteins found at their tips. Instead, most of the proteins that distinguish cancer cells from healthy cells are found within cells, where the immune system cannot detect them.
For many years, KRAS – despite its prevalence in cancers – was considered untreatable. The modified version of KRAS, which drives the growth of cancer cells, works inside the cells. It often has only one small change that distinguishes it from regular KRAS and does not have a readily visible spot on its drug-binding structure. But over recent decades, Forks has performed detailed protein analyzes and discovered a hidden pocket in mutant KRAS that any drug could block. His work contributed to the development and approval of sotorasib.
However, suturacip does not help all patients with KRAS mutations, and some tumors that shrink become resistant and start growing again. Shokat, Crick, and their colleagues wondered if there was another way to target KRAS.
In the new work, the team showed that when ARS1620 — a KRAS target drug similar to sotorasib — binds to mutant KRAS, it not only prevents KRAS from affecting tumor growth. It also persuades the cell to recognize ARS1620-KRAS as a foreign molecule.
“This mutant protein usually flies under the radar because it’s so similar to a healthy protein,” says Crick. “But when you stick that drug to it, it gets spotted right away.”
This means that the cell processes the protein and moves it to its surface as a signal to the immune system. KRAS that was hidden inside is now displayed as an ‘eat me’ tag on the outside of tumor cells.
With mutant KRAS shifting from inside to outside cells, the UCSF team was then able to screen a library of billions of human antibodies to identify those that can now recognize this KRAS marker. Through studies of both isolated proteins and human cells, the researchers demonstrated that the most promising antibody identified could tightly bind to ARS1620 as well as to the ARS1620-KRAS complex.
Next, the group engineered an immunotherapy around this antibody, which prompted the immune system’s T cells to recognize KRAS flag and target cells for destruction. They found that the new immunotherapy could kill cancer cells containing mutated KRAS and treated with ARS1620, including those that had already developed resistance to ARS1620.
“What we’ve shown here is proof of principle that a cell that is resistant to current drugs can be killed by our strategy,” Shawkat says.
More work is needed in animals and humans before the treatment can be used clinically.
The researchers say the new approach could pave the way not only for combination therapies in cancers with KRAS mutations, but also other similar pairs of targeted drugs with immunotherapies.
“This is platform technology,” says Craik. “We would like to go after other targets that might also transport molecules to the cell surface and make them amenable to immunotherapy.”