Promising Pre-Clinical Results in the Killing of Cancer Cells Resistant to
Current KRAS-Targeted Treatments from UCSF Study
The human immune system is notably adept at avoiding tumor cells, who
construct physical barriers, don masks, and use molecular cunning to
restrain the immune system. Researchers from UC San Francisco have now
created a medication that gets past some of these obstacles and marks cancer
cells for immune system eradication.
A mutant form of the protein KRAS is attracted to the surface of
cancer cells by the novel treatment, which works as a "eat me" flag when combined with
the medicine. The immune system can then be stimulated by an immunotherapy
to successfully destroy all cells displaying this flag.
The immune system is already capable of identifying mutant KRAS, but it
often has trouble doing so. The immune system has a lot easier time
recognizing the protein when we add this signal, according to UCSF chemist
and Howard Hughes Medical Institute Investigator
Kevan Shokat, PhD, who helped lead the new research.
KRAS mutations are one of the most prevalent gene mutations in cancer,
present in roughly 25% of malignancies. Sotorasib, which the Food and Drug
Administration (FDA) has granted provisional clearance for use in treating
lung cancer, also targets mutated KRAS, and it is possible that the two
treatments may ultimately function well together.
Charles Craik, PhD, a lead study author and professor of pharmaceutical chemistry at
UCSF, stated, "It's intriguing to have a novel technique utilizing the
immune system that we can combine with targeted KRAS medicines." We believe
that cancer patients may experience deeper and longer responses as a
result.
Cancer Markers Turned Inside Out
Foreign cells are frequently identified by the immune system thanks to
peculiar proteins that protrude from their surfaces. However, there aren't
many distinctive proteins on the exterior of cancer cells. Instead, the
majority of the proteins that distinguish tumor cells from normal cells are
found inside the cells, out of reach of the immune system.
Despite the fact that KRAS is frequently found in tumors, it was long
thought to be intractable. The altered KRAS protein functions inside cells
to promote the development of tumor cells. It frequently only differs from
regular KRAS by a single minor mutation, and it lacks an obvious location on
its structure where a medication may attach. Shokat, however, has conducted
thorough investigations of the protein in recent years and found a druggable
area in mutant KRAS. His work aided in the creation and endorsement of
sotorasib.
But not all KRAS-mutant patients benefit from sotorasib, and some of the
tumors it does reduce develop resistance and recur. Shokat, Craik, and their
coworkers questioned if there was another strategy for inhibiting
KRAS.
In the latest research, the team demonstrates that ARS1620, a targeted KRAS
medication similar to sotorasib, binds to mutant KRAS and does more than
simply prevent KRAS from influencing tumor development. Additionally, it
induces the cell to identify the ARS1620-KRAS complex as an alien
substance.
Because it is so similar to the healthy protein, "this mutant protein is
frequently floating under the radar," claims Craik. But as soon as you link
this medicine to it, it becomes immediately apparent.
That indicates that the protein is processed by the cell and moved to its
surface as a warning to the immune system. The KRAS that was formerly
concealed within is now visible on the exterior of the tumor cells like a
"eat me" flag.
Potential Immunotherapy
The UCSF team was then able to scan a library of billions of human
antibodies to find those that could now detect this KRAS flag as the mutant
KRAS had moved from the inside to the exterior of cells. The most promising
antibody they had found could bind strongly to both the medication ARS1620
and the ARS1620-KRAS complex, the researchers demonstrated in testing on
both isolated protein and human cells.
In order to induce the immune system's T cells to identify the KRAS flag
and select cells for eradication, the team then developed an immunotherapy
centered around that antibody. They discovered that tumor cells with the
mutant KRAS gene and those treated with ARS1620, including those that had
previously established resistance to ARS1620, could be destroyed by the
novel immunotherapy.
According to Shokat, "What we've demonstrated here is proof of principle
that a cell resistant to the medications now available may be destroyed by
our technique."
Before the therapy might be employed in clinical settings, more testing in
both humans and animals is required. The novel strategy, according to the
researchers, may open the door to additional comparable combinations of
targeted medicines and immunotherapies as well as combination therapy for
malignancies with KRAS mutations.
Craik claims that this technology is a platform. "We'd want to pursue
additional targets that could similarly get compounds to the cell surface
and render them immunotherapy-friendly."
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 on the article in addition to Shokat and Craik.
Funding: The Howard Hughes Medical Institute, the Samuel Waxman Cancer
Research Foundation, The Mark Foundation for Cancer Research, The Damon
Runyon Cancer Research Foundation, The Innovation Ventures Philanthropy
Fund, and The Marcus Program in Precision Medicine all contributed to the
study's funding (DRG-2281-17).
Conflicts of interest: UCSF has a provisional patent application for this
work that names Craik, Shokat, Zhang, and Pohweder as inventors. Shokat is a
shareholder in the following companies as well as a consultant for them:
Revolution Medicines, Black Diamond Therapeutics, BridGene Biosciences,
Denali Therapeutics, Dice Molecules, eFFECTOR Therapeutics, Genentech/Roche,
Janssen Pharmaceuticals, Kumquat Biosciences, Kura Oncology, Mitokinin,
Nested, Type6 Therapeutics, Venthera, Wellspring Biosciences (Araxes
Pharma), Next
