Kevan 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
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 Research meeting 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
Kevan stood out as being in a class of his own, for his originality and creativity.
Frank McCormick, PhD
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.”