A New Way In: How Outside-the-box Science Sparked a Revolution in Targeting KRAS
Exactly one month after the landmark approval by the U.S. Food and Drug Administration of the RAS inhibitor daraxonrasib (Rasonque) for the treatment of pancreatic cancer, a pioneer in the KRAS inhibitor field received an important and timely recognition for his critical contributions to pancreatic cancer research that enabled the advent of the new generation of RAS-directed therapies.
Kevan M. Shokat, PhD, FAACR, was named the 2026 Stephenson Global Prize Laureate at the recent AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development, a global forum where more than 600 attendees from academia, medicine, industry, and patient advocacy came together to discuss the latest research developments that are improving the odds for patients with pancreatic cancer. Shokat is a professor at the University of California, San Francisco (UCSF) and at the University of California, Berkeley, and a Howard Hughes Medical Institute investigator.
The Stephenson Global Prize is a $1 million award presented by the Stephenson Global Pancreatic Cancer Research Institute (SGPCRI) to visionary scientists whose work has transformed pancreatic cancer research. The inaugural edition of the prize was bestowed upon another giant in the KRAS field, Frank McCormick, PhD, FAACR, in 2025.
“Dr. Shokat’s groundbreaking research exemplifies how fundamental science can redefine cancer medicine,” said Margaret Foti, PhD, MD (hc), the chief executive officer of AACR, in a news release. “As a Fellow of the AACR Academy, he is among an extraordinary group of scientists whose discoveries have fundamentally advanced our understanding and treatment of cancer. His pioneering work targeting KRAS helped catalyze an entirely new area of cancer drug development and has contributed to extraordinary momentum in the pursuit of therapies for RAS-driven cancers. AACR is delighted to join SGPCRI in recognizing his remarkable contributions and the profound impact that innovative cancer research can have on patients.”
During the honorary lecture, Shokat traced the history of discoveries that culminated in the design of the first generation of mutant-KRAS inhibitors in his lab, which eventually led to approved drugs and a portfolio of more than 90 different candidates currently in clinical development. He also illustrated the factors that made KRAS such a challenging drug target and how chemistry helped solve the puzzle.
KRAS was one of the first human oncogenes to be discovered in the early 1980s, when researchers identified KRAS mutations as cancer drivers. For a broader historical perspective, check out this previous post from 2022 commemorating the 40th anniversary of the discovery of the first human oncogenes.
Despite the enormous body of knowledge that had accumulated over the decades on the importance of KRAS as a target in cancer, with 2.5 million patients affected by KRAS-mutant cancers every year, it wasn’t until 2021 that the world saw a KRAS-targeted therapy approved, Shokat emphasized.
Why Did It Take So Long for Scientists to Break Through KRAS?
KRAS is a very small protein and lacks suitable pockets on its surface where drugs could bind. The most obvious approach to target it, Shokat said, would have been to block its enzymatic function as a GTPase. For comparison, he added, it only took nine years from the discovery of mutations in BRAF, an oncogene that is altered in melanoma, to the approval of the first drug targeting its enzymatic activity as a kinase in 2011. “Kinases are similar to GTPases, and there are about 100 different kinase drugs approved now,” said Shokat. “Why could we not apply what we learned about kinases to inhibit the KRAS GTPase?”
Unfortunately, KRAS’ ligands (GDP and GTP) are bound so tightly to the protein that no drug would be able to compete and displace them, he explained.
Then scientists got creative, Shokat noted, and tried to interfere with KRAS localization to the cell membrane—where it carries out its signaling functions—by blocking an enzyme called farnesyl transferase. Farnesyl transferase inhibitors were successful in shrinking tumors in preclinical models but failed in clinical trials in the late 90s because, as it turned out, the tumors could find a biological bypass mechanism around the block.
By that point, KRAS had earned its bad reputation as an undruggable protein, and it was clear that conquering it would require an out-of-the-box strategy to make a drug that could bind directly to it. That’s when Shokat started his journey in the KRAS field by joining UCSF, where McCormick, who recruited him, encouraged him to focus on resolving the challenge.
How a Chemist Cracked KRAS
Shokat’s research built on fundamental work by other scientists who elucidated the inner workings of KRAS and its sister proteins of the RAS family, which cycle between an active (GTP-bound) and an inactive (GDP-bound) state. Specifically, McCormick’s lab demonstrated that mutant RAS proteins have a defect in their “off” switch mechanism and tend to spend most of the time in the “on” state and continuously drive growth signal in cancer cells.
Further discoveries illustrated the impact of the most common group of KRAS mutations on the protein’s structure and its ability to be turned on and off. These mutations affect the 12th amino acid of the protein, causing the substitution of glycine with a different amino acid.
The key to unlocking KRAS was focusing on the mutant amino acid cysteine that is substituted in the KRAS G12C mutant, which is most common in lung cancer. Cysteine, Shokat explained, is a chemically reactive amino acid that can work as an anchor point for a drug.
Starting from a library of 500 compounds, Shokat and collaborators found a hit molecule that bound the mutant cysteine on KRAS (and not other cysteine residues). Through a long process of optimization and further studies, the scientists discovered that the drug candidate bound the inactive form of mutant KRAS and locked it in that state such that it could not cycle back to the active state. Therefore, this first class of KRAS inhibitors are known as off-state inhibitors.
Shokat and colleagues reasoned that this strategy, if successful, would lead to a drug that only inhibited the mutant KRAS, present only in the tumor cells, and would not inhibit RAS signaling in normal cells. Further research through a company the researchers started, called Araxes, led them to a much more potent molecule that shrank tumors in animals. “That was the first demonstration of tumor growth inhibition by a pharmacological agent for RAS,” Shokat said.
These developments created momentum across the industry, and two companies, Amgen and Mirati Therapeutics, developed their own covalent, G12C-specific inhibitors that also targeted the off-state of KRAS, Shokat said. These inhibitors were subsequently approved as sotorasib (Lumakras, 2021) and adagrasib (Krazati, 2022).
Eventually, RAS wasn’t so elusive of a target anymore. “There are more and more of these inhibitors in development,” Shokat continued. “We are seeing RAS drugs being compared head-to-head in clinical trials, which I think is a big step forward because it will tell what the best ones are that can benefit patients the most.”
Beyond G12C
What about other cancer types that carry different KRAS mutations, such as G12D, which is the most common one in pancreatic cancer? The same chemical approach used to target G12C would not work, Shokat explained, because the mutant amino acid in this case is aspartate, which has very different chemical properties than cysteine and does not provide a suitable handle for a covalent bond.
To solve this, several companies began to experiment with different chemical strategies. Shokat’s work had paved the way by revealing the presence of a previously unknown internal pocket that is conserved in all members of the RAS family of proteins, in which drugs can sit. This discovery inspired the researchers to pursue broader RAS-targeting strategies by designing drug molecules that could fit in the pocket and block RAS independently of the presence of a specific mutation. This line of research eventually led to the development of pan-RAS inhibitors, such as daraxonrasib, and many other molecules in the works.
Looking back at the enormous progress in the KRAS field, Shokat is pleasantly surprised by the impact of his discoveries. “When Frank [McCormick] told me about KRAS, I didn’t even appreciate how frequent those mutations were and that they drove the worst kinds of tumors,” he said in a conversation with Cancer Research Catalyst. “We just thought of KRAS as a protein and focused on how to target it with a drug. As we got to the first KRAS G12C-specific molecules, we realized there were many more avenues for different kinds of KRAS drugs. Even in 2013 [when the landmark paper demonstrating that KRAS could be selectively targeted was published in Nature], I had no idea that in 2026 a therapeutic like daraxonrasib would provide such benefit for patients with late-stage pancreatic cancer. That, you don’t dare hope, because it usually doesn’t happen.”
Setting the Stage for the Breakthrough: The Long Commitment of NCI to RAS Research
What transformed KRAS from an “undruggable” target into one that can be targeted pharmacologically for cancer treatment was a combination of ingenuity and decades of effort by the cancer research community in deciphering how RAS proteins function, how mutations alter their regulation, and what their three-dimensional structures look like.
Most of this work, including Shokat’s fundamental research, was supported by public funding from the National Cancer Institute (NCI). This video delineates some of the RAS research milestones enabled by NCI since the 1970s and culminating in 2013 with the establishment of the RAS Initiative, led by McCormick. The RAS Initiative created a hub, bringing together researchers from government, academia, and industry with the goal of developing therapies for RAS-driven cancers.
Although the currently approved RAS inhibitors have proven to be very effective for certain cancers, no single inhibitor is optimal for every RAS-driven cancer. Researchers continue to develop next-generation inhibitors to improve potency, overcome resistance, and address the different RAS mutations and cancer types.
Shokat’s lab remains focused on selectively targeting the KRAS G12D mutant. They devised another chemical strategy to allow drugs to attach to the aspartate residue. After many trials and errors, they solved the crystal structure of the KRAS-bound G12D-specific drug candidate. “This really was an exciting moment because G12D is the cancer mutation that drives most pancreatic cancers. And we have a drug that is unique to that,” he said. “We think these selected molecules, which have demonstrated promise in preclinical studies, will have a place in upcoming clinical trials.”
The Next Challenge
With funding support from the Stephenson Award, Shokat has taken on the next challenge in precision oncology: finding drugs that can reawaken tumor suppressor proteins, the cell’s built-in safety systems that guard against tumor development.
This goal comes with a new set of challenges. “Each tumor suppressor is its own category,” Shokat told Cancer Research Catalyst. “For example, while p53 acquires mutations, some other tumor suppressors are lost completely, and others become weakened in their function.”
The effort of reactivating tumor suppressor function will require more thinking outside of the box, but we know that Shokat and his team do not shy away from that.
One target they are studying is the tumor suppressor protein RB. RB keeps cell proliferation in check by binding and restraining the activity of the E2F transcription factor, which controls expression of genes required for DNA replication. When RB is bound to E2F, those target genes remain off, and the cell cannot proceed to the next phase of the cell cycle.
Cancer cells can disable the RB safeguard mechanism by losing expression of the protein or interfering with its function, and Shokat’s team is working on restoring that function. “We are trying to bind molecules to parts of RB that will make it hold on to E2F and silence it harder,” Shokat explained.
Borrowing the chemical approach that uses cysteine as a foothold for KRAS, the lab is also successfully developing mutant p53-targeting drugs. Their goal is to restore the function of p53, the most commonly mutated protein in cancer.
Cancer Research Catalyst continued the conversation with Shokat to bring you a deep dive into the new era of p53-targeting science. Stay tuned to learn more!
