Death Star’ protein has a weak spot

Researchers have identified a second weakness in a cancer-promoting protein called KRAS. An analysis of 26,000 mutations revealed two vulnerable spots in the protein: one that has already been exploited by existing KRAS inhibitors, and a novel location called cavity 3. Like the Death Star from Star Wars, the KRAS was thought to be impenetrable — but a complete blueprint of the spherical protein has helped researchers to find a rare weak point.

Four scientists from Barcelona have created the first map of the vulnerable sites of the KRAS gene, whose mutations, often associated with smoking, cause millions of tumors

One in two men and almost one in three women will have cancer during their lifetime. In at least one in 10 cases, the tumor will be driven by mutations in the KRAS gene, discovered in 1982, but so devilishly complex that the scientific community has spent four decades trying to find its Achilles. Mutations in KRAS are behind almost 90% of pancreatic cancer cases, 40% of colon cancers and 35% of lung cancers. A team from the Center for Genomic Regulation in Barcelona has finally managed to create a complete map of its weaknesses. A preview of the research was published Monday in the journal Nature, a showcase of the best world science.

Genes are stretches of DNA with the instructions for making a protein. The KRAS gene is the manual for generating the KRAS protein, a kind of switch that causes the cell to divide. Uncontrolled activation of KRAS causes cells to run amok, multiply and cause cancer. For decades, it seemed impossible to target this protein with drugs. However, in 2021, the U.S. pharmaceutical company Amgen received FDA approval for sotorasib, an effective drug against lung cancer in people who have a specific mutation in the KRAS gene, which is associated with damage caused by smoking. Biochemist Ray Deshaies, scientific vice-president of Amgen, explained at a press conference that “[the delay of over four decades] wasn’t because we didn’t know what we wanted to do, which was inhibit the mutation in KRAS, it’s just that we had no idea how to do it...”

...The authors of the new study explain that the KRAS protein is like the Death Star, the unconquerable space station from the Star Wars film saga. “The protein is quite spherical and has very few sites that you could imagine as binding points for a drug,” says South African bioinformatician André Faure, who works at the Barcelona institution. “It was considered to be impenetrable,” emphasizes his colleague Albert Escobedo. In the movie Star Wars, the good guys got a blueprint of the Death Star and the hero Luke Skywalker managed to hit its only weak point. The Center for Genomic Regulation team has now obtained the complete blueprint of KRAS...