Scientists design breakthrough drug to fight deadly pancreatic cancer mutation

Scientists have discovered a new way to neutralize a deadly protein that also appears in lung, breast and colon cancers.

Researchers at the University of California, San Francisco have designed a drug candidate that could help make pancreatic cancer, which is almost always fatal, treatable and even curable.

This new molecule, called K-Ras G12D, is responsible for nearly half of all pancreatic cancer cases and appears in some forms of lung, breast, and colon cancer. , permanently altering subtle cancer-causing mutations.

Although pancreatic cancer is less common than other cancers, it is highly deadly due to the lack of treatment options, claiming more than 50,000 lives in the United States each year.

“We have been working for 10 years to bring treatments for pancreatic cancer up to speed with treatments for other cancers,” said Kevan Shokat, a professor in the Department of Cellular and Molecular Pharmacology who led the study. the doctor said. “This breakthrough discovery is the first to target G12D and gives us a solid foothold in the fight against this devastating mutation.”

The findings of this study were published on March 5, 2024. natural chemical biology.

Shokat and his colleagues developed the first cancer drug to block another K-Ras mutation, G12C, in 2013. Since then, two treatments have been approved for use in lung cancer and breast cancer, but advances have not moved the treatment needle. Pancreatic cancer.

very common mutation

K-Ras mutations are highly prevalent in pancreatic cancer, explaining 90% of cases. Approximately half of these mutations are G12D, which differs from most other K-Ras mutations by a single amino acid substitution.

There is this slight difference between healthy proteins and cancer-causing proteins. glycine Transforming (G) into aspartic acid (D) was a major challenge for chemists.

Few molecules can detect the difference between cancer-causing aspartate and glycine. To develop good treatments, we need drugs that act only on tumor cells and not on healthy cells. ”

Kevan Shokat, Ph.D., Professor, UCSF Department of Cellular and Molecular Pharmacology

Shokat's team envisioned a molecule that would fit into the pocket of the K-Ras protein and bind firmly and irreversibly to the rogue aspartate. Shokat's surge of research following his 2013 discovery has made it possible to develop chemical templates that reliably invade the corners of proteins.

“Once we knew the structure of the molecule, we knew it was in the right place in the protein,” Shokat says. “Then we can explore the little nooks and crannies we need to discover the chemistry of aspartic acid.”

Could molecular bending lead to treatments?

Scientists investigated dozens of chemicals.

“It's like climbing a new route on a mountain. You may be strong, but your arm length limits what you can do,” Shokat said. “It took a lot of trial and error to fine-tune the branches of these molecules to place them in an incredibly tight space around G12D. Some came close, but then we failed, and I had to start all over again.”

In the end, they discovered the winning molecule. It settled into the appropriate corner of K-Ras and bent into a new shape that reacted strongly with aspartic acid.

This molecule braked G12D-induced tumor growth not only in animal models of human cancer but also in cancer cell lines. And it didn't attack healthy proteins.

Scientists are currently optimizing the molecule to be durable enough to fight cancer in humans. With the traction gained from this study, new treatments for pancreatic cancer could enter clinical trials within as little as two to three years, Shokat said.

“We have learned a lot from other targeted therapies and know how to quickly translate these discoveries into the clinic,” said Margaret Tempero, M.D., director of the UCSF Pancreas Center. “Effective drugs targeting K-RAS G12D could be transformative for patients with pancreatic cancer.”