UC San Francisco researchers have designed a candidate drug that could help make pancreatic cancer, which is almost always fatal, a treatable, perhaps even curable, condition.
The new drug candidate permanently modifies a wily cancer-causing mutation, called K-Ras G12D, that is responsible for nearly half of all pancreatic cancer cases and appears in some forms of lung, breast and colon cancer.
Pancreatic cancer is less common than these other cancers, but the lack of treatment options makes it more deadly, and it claims more than 50,000 lives each year in the United States.
“We’ve worked for 10 years to bring pancreatic cancer therapies up to speed with therapies for other cancers,” said Kevan Shokat, PhD, a professor in the Department of Cellular and Molecular Pharmacology who led the work. “This breakthrough is the first to target G12D and gives us a firm foothold to fight this devastating mutation.”
The findings appear March 5, 2024, in Nature Chemical Biology.
Shokat and his colleagues developed the first cancer drugs to stop a different K-Ras mutation, G12C, in 2013. Since then, two therapies have been approved for use in lung and breast cancer, but the advance didn’t move the needle for treating pancreatic cancer.
An extremely common mutation
K-Ras mutations are extremely common in pancreatic cancer, explaining 90% of cases. About half of these mutations are G12D, which differs from most other K-Ras mutations by a single amino acid substitution.
This difference between healthy and cancer-causing proteins, in which glycine (G) becomes aspartate (D), presented a monumental challenge for chemists.
“There are very few molecules out there that can sense the difference between the cancer-causing aspartate and the glycine,” Shokat said. “To make good therapies, we need drugs that work on the tumor cells only, without affecting healthy cells.”