Penny Wagnon walks into a San Francisco conference room. Outside, a February cold snap sharpens the breeze off the Bay. Wagnon weaves through tables arranged before a small stage and finds a seat.
“Hi, I’m Penny,” she says cheerily. “I have lung cancer.”
Her tablemates introduce themselves: name then diagnosis. A young woman takes her turn. “I have colorectal cancer,” the 31-year-old replies quietly. A heavy silence follows.
It is a meeting of accidental kin — each possesses a mutation in a protein known as KRAS. KRAS mutations drive about 30% of cancer cases, especially cancers of the lung, colon, and, overwhelmingly, the pancreas.
Terri Conneran was diagnosed with KRAS-positive lung cancer in 2017. Finding no patient support groups and scant information, she formed her own: The KRAS Kickers.
Armed with what she jokes is a business degree from a “third-rate college,” Conneran taught herself the science behind KRAS and connected with experts like UC San Francisco Cellular and Molecular Pharmacology Professor Kevan Shokat, PhD, and Frank McCormick, PhD, FRS, professor and former director of the UCSF Helen Diller Comprehensive Cancer Center. Streaming from her North Carolina living room, Conneran invited Shokat regularly to patient webinars.
Today, “Kickers” from Arizona to Massachusetts have traveled to UCSF. Conneran takes the stage. Seated in front, Shokat snaps a photo. Behind him is the young woman with colorectal cancer who hopes to find a clinical trial and access experimental treatments unthinkable just a decade ago. As the crowd quiets, Wagnon leans toward her and whispers: “This is why I am so excited to be here — this is where they found the pocket.”
Today, “Kickers” from Arizona to Massachusetts have traveled to UCSF. Conneran takes the stage. Seated in front, Shokat snaps a photo. Behind him is the young woman with colorectal cancer who hopes to find a clinical trial and access experimental treatments unthinkable just a decade ago. As the crowd quiets, Wagnon leans toward her and whispers: “This is why I am so excited to be here — this is where they found the pocket.”
The ‘Mount Everest’ of cancer drug targets
In the factories of our cells, proteins are the workers carrying out essential tasks. In healthy cells, the KRAS protein helps control cell growth, toggling “on” and “off” like a switch. But some mutations cause KRAS to get stuck in the “on” position, promoting unchecked growth that can lead to cancer. Many medicines work by binding to pockets on wayward proteins — like a key to a lock — but KRAS’s slippery, shape-shifting surface was impervious for more than 30 years.
“It was the Mount Everest of all drug targets in cancer,” Shokat remembers.
KRAS was deemed “undruggable” — and young scientists were warned that pursuing it was career suicide. Pharmaceutical companies largely abandoned the quest, while researchers instead tried, with limited success, to block its downstream cancer-driving signals.
But a small group of UCSF scientists persevered, and in 2013, Shokat discovered KRAS’ first druggable pocket — building on federally funded insights and technologies developed by McCormick, Pharmaceutical Chemistry Professor Jim Wells, PhD, and others at UCSF. Their dogged pursuit gave rise to a new class of cancer drugs. The first treatment for KRAS-positive lung cancer followed in 2021. This year, the Food and Drug Administration approved the first medicine shown to substantially extend life expectancy for pancreatic cancer patients with KRAS.
“Kevan used all the tools of modern chemistry and biology to crack open a discovery that has profoundly impacted human health,” says UCSF Chancellor Sam Hawgood, MBBS. “His success shows how support for fundamental science leads to big breakthroughs.”
Today, more than 60 other drugs targeting KRAS and closely related genes are in development.