“The chemists here call mutated KRAS the Death Star,” says Rusty Lipford, director of inflammation and oncology research with the biotechnology firm Amgen. But KRAS is no space station. It’s a lethal, misshapen protein that jumpstarts a pathway that drives almost a quarter of all cancers, and it has baffled scientists who have spent almost four decades searching for weak spots in its armor. “It’s been an extraordinary challenge and a saga that began before I was born,” Lipford says.
The Death Star is still far from destroyed and KRAS still poses a severe threat. But thanks to recent advances, researchers targeting the mutated protein now have the blueprints and a potential line of attack. Crucially, these include investigational drugs designed to block the activity of a specific mutant version of KRAS, many of which are now being studied for various cancers.1 “For a very long time the field viewed KRAS as an undruggable target,” says Lipford. “But now we may have a real path forward.”
The struggle against KRAS began as soon as the gene was discovered in the 1960s, when virologists Jennifer Harvey and Werner Kirsten isolated two viruses that caused tumors in rats and other rodents. The genes responsible were named HRAS and KRAS for their discoverers and because they caused sarcomas—cancers of bone, soft tissues and connective tissues—in rats.2
By the 1980s, mutations in three separate RAS genes—KRAS, HRAS and NRAS—were shown to turn healthy human cells cancerous and were labeled as the first oncogenes. As further advances in genetics revealed how molecular changes to DNA could generate and sustain human cancers, such oncogenes and their protein products became a focus of research.
By the late 1990s, scientists had managed to identify drugs that worked against mutant proteins that function in specific signaling pathways that cancer cells rely on—a step that ushered in a revolutionary new class of cancer treatments. Until then, chemotherapies killed healthy cells alongside cancer cells, triggering brutal side effects. In contrast, the new targeted therapies, the first of which was approved in 2001, homed in on abnormal proteins that cancer cells rely on. As a result, these therapies had the potential for fewer side effects and improved patient outcomes.
Today genetic screening for tell-tale mutations, followed by targeted therapy, has become standard care for many cancers, such as breast cancers with BRCA1/2 alterations, and colorectal and lung cancers with EGFR mutations.
How RAS resists
Scientists have found RAS oncoproteins much harder to target than other oncoproteins. That’s a real problem because studies have shown that abnormal RAS proteins—and most commonly the KRAS protein—often drive three of the four most lethal, hard-to-treat cancers, including lung, colorectal and pancreatic cancer.3 A single KRAS mutation, called the G12C mutation, is the most common KRAS mutation in non-small cell lung cancer, and is found in about one in eight cases in the United States.
Changes to the KRAS protein cause such havoc because of the central role it plays in how our cells function. The molecule detects incoming signals and passes messages on to the next protein as part of a chain of biochemical reactions that controls cell behaviors that malfunction in cancer, including growth and differentiation.4 “It acts as a central master switch,” Lipford says. “Cancer-causing mutations leave this protein stuck in the on position, which can cause uncontrolled cell growth,” he adds. So, cancer scientists have been trying to find a way to turn it off.
Drugs that successfully interfere with the activity of proteins are usually small molecules that can bind indentations—so-called pockets—on the protein surface. “But the exterior of KRAS is more like a billiard ball,” Lipford says. The smooth surface of the protein, with no obvious pocket in which to lodge a possible drug, earned KRAS the reputation as undruggable.3 Discouraged researchers switched to investigating alternative routes to address the way it caused cancers, such as targeting other proteins involved in the same cellular pathways.
The picture changed in late 2013 when chemists at the University of California, San Francisco, led by Kevan Shokat, showed for the first time that a small molecule could lock on to a mutant form of KRAS. Specifically, the small molecule bound to a distinctive feature of an important mutant form, where an amino acid called a glycine in the normal protein is replaced by a cysteine. The switch happens at what chemists call the 12-position, which gives the mutant KRAS protein its name, G12C. And the cysteine group carries a sulfur atom that serves as a landing pad for a potential drug.
“There’s a quirk of chemistry that makes this particular mutation targetable in this way,” says Julian Downward, an oncogene researcher at the Francis Crick Institute in London. “The amino acid replacement that’s caused by the mutation is chemically active. If you had another amino acid mutation at that location, then it wouldn’t work.”
The discovery energized the field, Downward says, and galvanized ongoing efforts at several pharmaceutical companies to hunt for suitable candidate drugs that could bind the same G12C pocket and thus limit the abnormal protein’s cancerous activity.
In 2019, researchers at Amgen reported in Nature the discovery of a potential drug that chemically links to the inactive form of mutant KRAS and prevents it from shifting to its active form. It does not interfere with the functioning of normal KRAS molecules, which carry on their vital work. The compound is now in clinical trials as a potential new treatment for non-small cell lung cancer with the KRAS G12C mutation.5
“KRAS has always been incredibly tough,” says Ravi Salgia, a medical oncologist at the City of Hope Comprehensive Cancer Center in Duarte, California, who has worked in the field for 30 years. “It’s really nice to see that there are now these small molecule inhibitors in clinical trials.”
- Moore AR, et al. Nat Rev Drug Discov. 2020;19:533-552.
- Weiss, RA. Cancer Metastasis Rev. 2020;39:1023–1028.
- Cox AD, et al. Nat Rev Drug Discov. 2014;13:828-851.
- Ferrer I, et al. Lung Cancer. 2018;124:53-64.
- Canon J, et al. Nature. 2019;575:217-223.