UCSF’s Kevan Shokat Wins Stephenson Prize for Cancer Breakthrough

Kevan Shokat, PhD, a professor of Cellular and Molecular Pharmacology at UC San Francisco who discovered how to disable KRAS, a seemingly unstoppable cancer-driving protein, has won the Stephenson Global Prize for research in pancreatic cancer.

The prize, which comes with $1 million, was given at the American Association for Cancer Researchmeeting in San Diego on Sept. 26.

Shokat used chemistry to control proteins that govern important cellular processes like growth. In 2013, he discovered a way to block KRAS, a growth-signaling protein that is mutated in many cancers. The protein has a smooth, slippery surface that makes it extremely hard to target with drugs, and the cancer field had all but given up on finding a way to stop it.

Shokat found a hidden vulnerability, and drug companies vigorously pursued the lead. The first KRAS inhibitor was approved for lung cancer in 2021, and more than 60 other drugs targeting the RAS gene family are now in development.

“It’s a beautiful example of someone persevering on a seemingly intractable problem,” said UCSF Chancellor Sam Hawgood, MBBS. “He used all the tools of modern chemistry and biology to eventually crack open a discovery that has — and will have — a profound impact on human health.

“Kevan has received funding for many years from the National Institutes of Health (NIH) and the Howard Hughes Medical Institute, and his success shows how support for fundamental science leads to big breakthroughs.”

Cracking cancer’s “undruggable” target: UCSF’s Kevan Shokat, PhD, explains how his team discovered a hidden vulnerability in KRAS, opening the door to a new generation of cancer treatments.

Cancer’s “On” Switch

KRAS behaves like a switch inside cells. When it’s on, cells grow. This is needed for normal growth and wound healing. But when the gene is mutated, the protein can get stuck in the “on” position, causing cells to grow out of control. Such mutations cause about 30% of all cancers and nearly 90% of pancreatic cancers.

Frank McCormick, PhD, then-director of the UCSF Helen Diller Family Comprehensive Cancer Center and a pioneer in how KRAS sends signals to promote cancer cells, had watched a generation of scientists fail in their attempts to find drugs that would attach to KRAS. But he encouraged Shokat to keep trying.

“Kevan stood out as being in a class of his own, for his originality and creativity,” McCormick said. “We discussed targeting KRAS as soon as Kevan arrived, because the clinical need is enormous, and so is the intellectual challenge of finding a drug that could bind to a small protein with no obvious pockets.”

A Sticky Spot on a Slippery Suspect

Shokat partnered with Jim Wells, PhD, a professor of Pharmaceutical Chemistry in the UCSF School of Pharmacy. Wells had pioneered screening methods to find compounds that could grasp onto malfunctioning proteins. KRAS was the most difficult of them all. Described as a “greasy ball,” it seemed impossible to get ahold of.

Shokat and Wells focused on a cancer-causing mutant of KRAS called G12C, which has a cysteine amino acid in the place of a glycine — creating a chemically “sticky” spot that drug compounds could bond to.

“It took real courage to tackle a problem that so many scientists had given up on,” Wells said. “Kevan had this remarkable insight to use G12C as a chemical handle for discovering new drug candidates against KRAS.”

The team attached hundreds of candidate drugs to the cysteine on KRAS, one at a time, with breakable chemical links, or tethers. If a candidate failed to grasp KRAS, the tether would break and the drug candidate would fall off. But if its grip was strong, the tether would hold.

ImageKevan Shokat, PhD, looks at a digital image of a KRAS Q61h inhibitor with Julius Pampel, a graduate student in Shokat’s lab, at Genentech Hall on the UCSF Mission Bay Campus. Photo by Erin Lubin

A Molecular Hug Changes Everything

By early 2010, the drug screen had found a drug candidate that seemed to grip KRAS firmly, locking the switch in the “off” position. But Shokat needed proof that the hold was stable.

His team spent months concentrating KRAS with the drug candidate in ever smaller volumes of liquid until the pair formed perfect crystals, “like diamonds,” Shokat recalled. Then they used x-ray crystallography to blast x-ray beams against the crystal to make shadows so they could determine the exact shape of the interaction.

Finding a Pocket of Hope

KRAS was considered one of cancer’s most impossible drug targets. See how UCSF scientists found a hidden pocket that changed cancer treatment.

On a December night that year, a postdoc in Shokat’s lab emailed him the reconstructed crystal structure. It showed the small-molecule drug candidate wedged into an unexpected pocket in KRAS, as if KRAS was hugging it. The drug candidate had coaxed KRAS to shape-shift and reveal a pocket.

“We were shocked — no one had seen this pocket before,” Shokat recalled. “But everyone had been searching for the pocket first, intending to design a drug to fit in it. We started with the drugs, thanks to Jim’s incredible drug library, and the right drug had revealed the pocket.”

A New Era in Cancer Treatment

Shokat’s team spent a few years improving the drug candidate, then published their discovery in 2013. They had found the first drug candidate that directly blocked KRAS G12C by keeping it locked in the “off” position. It forever changed how KRAS-driven cancers — with 2.5 million new diagnoses every year — would be treated.

Over the years, that drug evolved into ever more potent KRAS G12C blockers. A direct descendant of this drug earned approval from the Food and Drug Administration (FDA) for lung cancer in 2021. The breakthrough also inspired research teams around the world to find other KRAS vulnerabilities that could be targeted across its many cancer-causing mutations.

One recent example, a pancreatic cancer therapy called daraxonrasib, doesn’t rely on a pocket to block KRAS. Instead, it glues a second protein to KRAS when the switch is already turned on, preventing it from interacting with other growth signals. And it is effective against many of the cancerous mutations of KRAS, including G12C, as well as other mutated RAS proteins that are linked to different cancers.

In May 2026, the company behind daraxonrasib, Revolution Medicines, which Shokat co-founded, announced the results of its Phase III trial at the American Society of Clinical Oncology meeting in Chicago.

Although it is not yet a cure, the new therapy doubled survival time for patients with advanced pancreatic cancer from 6 to 13 months. The company’s announcement drew a standing ovation from cancer researchers who had been waiting for decades for a breakthrough like this.

Three months later, daraxonrasib was approved by the FDA.