Pancreatic tissue. Credit: UCSF
Key points:
- Researchers designed a candidate drug that targets the cancer-causing G12D mutation in K-Ras that is found in nearly half of all pancreatic cancer cases.
- After going through dozens of chemicals, the team found a molecule that settled in the corner of K-Ras and caused it to bend into a new shape that prevented tumor growth in cancer cell lines and an animal model of human cancer.
- Researchers are working to optimize the molecule to be durable enough to fight cancer in the human body as KRAS is implicated in pancreatic, lung, breast, and colon cancers.
Researchers have designed a candidate drug that could help make pancreatic cancer a treatable condition. Their findings, detailed in Nature Chemical Biology, reveal a new way to disarm a deadly protein that also appears in lung, breast, and colon cancers.
The new molecule targets a cancer-causing mutation in K-Ras that is found in about 90% of all pancreatic cancer cases. About half of these mutations are G12D where the mutated protein differs by a single amino acid substitution of a glycine (G) to an aspartate (D). There are very few molecules that are sensitive enough to identify the difference between the cancer-causing aspartate and the glycine, but the research team wanted to develop a molecule that could fit into the pocket of the K-Ras protein to firmly and irreversibly bind the aspartate.
In the search for this elusive molecule, the team went through dozens of chemicals.
“It’s like climbing a new route on a mountain, you may be strong but the lengths of your arms limit what you can do,” said Kevin Shokat, professor at the University of California, San Francisco. “It was a lot of trial and error, tweaking the branches of these molecules to position them in this incredibly tight space around G12D.”
The team did find a molecule that settled into the appropriate corner of K-Ras and caused it to bend into a new shape that reacted strongly with the aspartate. Their new molecule stopped cancer tumor growth from G12D in cancer cell lines and in an animal model of human cancer. Importantly, the molecule never attacked healthy proteins.
Researchers are working to optimize the molecule to be durable enough to fight cancer in the human body. Shokat and his team hope to bring new therapies for pancreatic cancer to clinical trials in the next two to three years.
“We’ve learned a lot form other targeted therapies and know how to quickly translate discoveries like these for the clinic,” said Margaret Tempero, director of the UCSF Pancreas Center. “An effective drug targeting KRAS-G12D could be transformative for patients with pancreatic cancer.”