Kevin Shannon, MD. Photo by Cindy Chew
Pharmaceutical, biotech and academic laboratories long have tried to develop drugs to target Ras. Most of the efforts focused on K-Ras, which is one of the three different types, or “isoforms,” of Ras – the others are N-Ras and H-Ras – and is the most
“About 85 percent of Ras mutations involve K-Ras,” said Kevin Shannon, MD, a UCSF professor of pediatrics who holds the Roma and Marvin Auerback Distinguished Professorship in Pediatric Molecular Oncology.
Many of the challenges researchers face in developing Ras drugs have to do with how the protein works.
Ras proteins are small enzymes that normally bind to the biomolecule GTP. When bound to GTP, Ras is considered to be in an “on” state because it stimulates a cascade of other protein interactions within cells that ultimately drive their growth.
The problem is that mutant Ras proteins grip on very tightly to GTP, which prevents them from converting GTP to another biomolecule, GDP. As a result, they are constantly in an “on” state.
“There have been a lot of different ways that people have tried to tackle this problem,” Shannon said. “One has been trying to develop drugs that restore normal Ras protein functions such as hydrolyzing GTP to GDP. That has proven to be extremely difficult.”
Some scientists have taken a different tack and tried to develop molecules that compete with GTP for the attention of mutant Ras proteins, but such approaches have also failed.