For more than 30 years, the KRAS protein was called the “Mount Everest” of cancer drug targets: everyone knew it drove cancers, but no drug could touch it. A new account from UCSF tells how a small team of scientists finally cracked it.

In 2013, chemist Kevan Shokat and colleagues discovered a hidden pocket in the KRAS G12C mutation. Using a chemical tethering strategy developed with Jim Wells, they found a molecule that locked KRAS in its “off” position. Young scientists had been warned the quest was career suicide.

The discovery led to the first KRAS drug approval for lung cancer in 2021. This year, the FDA approved daraxonrasib, the first medicine shown to substantially extend life for pancreatic cancer patients with KRAS mutations. In a phase 3 trial of 500 patients, median survival doubled to 13.2 months versus 6.7 on chemotherapy.

Shokat recently won the $1M Stephenson Prize. More than 60 drugs targeting KRAS and related genes are now in development.