Tumor cells are notoriously good at evading the human immune system; they put up physical walls, wear costumes and handcuff the immune system with molecular tricks. Now, UC San Francisco researchers have developed a drug that overcomes some of these barriers, marking cancer cells for destruction by the immune system.
The new therapy, described in Cell Cancer, brings a mutated version of the KRAS protein to the surface of cancer cells, where the drug-KRAS complex acts as an “eat me” flag. An immunotherapy can then coax the immune system to effectively eliminate all cells carrying that flag.
UCSF chemist Kevan Shokat talks with graduate student Megan Moore in his lab. Photo by Noah Berger
“The immune system already has the potential to recognize mutated KRAS, but it usually doesn’t find it very well. When we put this marker on the protein, it becomes much easier for the immune system,” said the UCSF chemist and researcher at Howard Hughes Medical Institute Kevan Shokat, PhD, who also helped lead the new work.
KRAS mutations are found in about a quarter of all tumors, making them one of the most common genetic mutations in cancer. Mutated KRAS is also the target of sotorasib, which the Food and Drug Administration (FDA) has given preliminary approval for use in lung cancer, and the two approaches may end well in combination.
“It’s exciting to have a new strategy that takes advantage of the immune system that we can combine with KRAS-targeted drugs,” said Charles Craik, PhD, 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.”
Turning cancer markers inside out
The immune system normally recognizes foreign cells because of unusual proteins sticking out of their surfaces. But when it comes to cancer cells, there are few unique proteins found on the outside. Instead, most of the proteins that differentiate tumor cells from healthy ones are inside the cells, where the immune system cannot detect them.
For many years, KRAS, despite how common it is in cancers, was considered undruggable. The mutated version of KRAS, which drives tumor cell growth, operates inside cells, often has only a small change that differentiates it from normal KRAS, and had no clear place in its structure because a drug s united But over the past few decades, Shokat conducted detailed analyzes of the protein and discovered a hidden pocket in mutated KRAS that a drug could block. Their work contributed to the development and approval of sotorasib.
Charles Craik, PhD
Sotorasib, however, does not help all patients with KRAS mutations, and some of the tumors that shrink become resistant and start growing again. Shokat, Craik and their colleagues wondered if there was another way to target KRAS.
In the new work, the team shows that when ARS1620, a targeted KRAS drug similar to sotorasib, binds to mutated KRAS, it not only blocks KRAS from affecting tumor growth. It also causes the cell to recognize the ARS1620-KRAS complex as a foreign molecule.
“This mutated protein usually flies under the radar because it’s so similar to the healthy protein,” says Craik. “But when you attach this drug to it, it’s detected immediately.”
This means that the cell processes the protein and moves it to its surface, as a signal to the immune system. KRAS that was once hidden inside is now displayed as an “eat me” flag on the outside of tumor cells.
A promising immunotherapy
By switching mutated KRAS from inside to outside cells, the UCSF team was able to screen a library of billions of human antibodies to identify those that could now recognize this KRAS flag. The researchers showed with studies on isolated proteins and human cells that the most promising antibody they had identified could bind strongly to the drug ARS1620 as well as to the ARS1620-KRAS complex.
When this drug is connected to it, it is detected immediately.
The group then designed an immunotherapy around this antibody, coaxing the immune system’s T cells to recognize the KRAS flag and target cells for destruction. They found that the new immunotherapy could kill tumor cells that had mutated KRAS and were treated with ARS1620, including those that had already developed resistance to ARS1620.
“What we’ve shown here is proof of principle that a cell resistant to current drugs can be killed by our strategy,” says Shokat.
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 treatments in cancers with KRAS mutations, but also other similar pairings of targeted drugs with immunotherapies.
“This is a platform technology,” says Craik. “We would like to pursue other targets that can also move molecules to the cell surface and make them susceptible to immunotherapy.”
Authors: In addition to Shokat and Craik, Ziyang Zhang, Peter J. Rohweder, Chayanid Ongpipattanakul, Koli Basu, Markus F. Bohn, Eli J. Dugan, Veronica Steri and Byron Hann of UCSF were also authors of the paper.
Funding: The study was supported by the Damon Runyon Cancer Research Foundation
(DRG-2281-17), the National Institutes of Health (T32 GM 064337, P41-GM103393), the Samuel Waxman Cancer Research Foundation, the Mark Foundation for Cancer Research, the Howard Hughes Medical Institute, the Innovation Ventures Philanthropy Fund, and the Marcus Program in Precision Medicine.
Conflicts of interest: Craik, Shokat, Zhang, and Pohweder are inventors on a provisional patent application covering this work and owned by UCSF. Shokat is also an inventor on other patents and related patent applications, and is a consultant and shareholder in the following companies: Revolution Medicines, Black Diamond Therapeutics, BridGene Biosciences, Denali Therapeutics, Dice Molecules, eFFECTOR Therapeutics, Erasca, Genentech/Roche , Janssen. Pharmaceuticals, Kumquat Biosciences, Kura Oncology, Mitokinin, Nested, Type6 Therapeutics, Venthera, Wellspring Biosciences (Araxes Pharma), Nextech, Radd, Totus, Vicinitas, Turning Point, Ikena, Initial Therapeutics, Vevo and BioTheryX.
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