One in two men and almost one in three women they will have cancer throughout his life. In at least one in 10 cases, the tumor will be driven by mutations in the gene KRAS, discovered in 1982, but so devilishly complex that the scientific community has been trying to reveal its Achilles heel for four decades. The alterations in KRAS are behind almost 90% of pancreatic cancer cases, 40% of colon cancer cases and 35% of lung cancer cases. A team from the Center for Genomic Regulation in Barcelona has finally managed to create a complete map of its weaknesses. Its trailer is published this Monday in the magazine Natureshowcase of the best world science.
Genes are simply stretches of DNA with the instructions for making a protein. The Gen KRAS It is the manual for generating the KRAS protein, a kind of switch that makes the cell divide. Uncontrolled activation of KRAS causes cells to run amok, multiply and generate cancer. For decades, this protein was considered an impossible target to treat with drugs. However, in 2021, the American pharmaceutical company Amgen achieved authorization of the sotorasib, an effective drug against lung cancer in people who have a specific mutation in the KRAS gene, associated with damage caused by smoking. The biochemist Ray Deshaiesvice president of science at Amgen, summed it up candidly last year: “[El retraso de casi cuatro décadas] It was not because we did not know what we wanted to do, which was to inhibit KRAS, but because we had no idea how to do it,” he acknowledged.
The key to advances is allosterism, a phenomenon considered “the second secret of life,” in the words of its discoverer, the French biologist Jacques Monod, who won the 1965 Nobel Prize in Medicine for it. DNA would be the first secret. Monod realized that proteins had some kind of hidden buttons that changed their function. Finding these springs is not easy. The water molecule, for example, has only two hydrogen atoms and one oxygen atom (H₂O). The KRAS protein, on the other hand, has 939 carbon atoms, 1,516 hydrogen, 260 nitrogen, 291 oxygen and 10 sulfur (C₉₃₉H₁₅₁₆N₂₆₀O₂₉₁S₁₀). It is a chemical giant that has been impregnable for decades.
The authors of the new study resort to a classic comparison. The KRAS protein, they explain, is like the Death Star, the unconquerable space station from the film saga Star Wars. “The protein is quite spherical and has very few sites that you can imagine as binding points for a drug,” says the South African bioinformatician. Andre Faure, who works at the Barcelona institution. “He considered himself impenetrable,” emphasizes his colleague. Albert Escobedo. In the film Star Wars, the good guys managed to get a plan of the Death Star and the hero Luke Skywalker managed to sneak an accurate shot into the only weak point. The Center for Genomic Regulation team has now obtained the complete blueprint of KRAS.
The researchers have used a new technique to analyze the effect of 26,000 mutations on the protein structure, instead of dozens as was usual with previous tools. Their results confirm an already known weak point, the one used by sotorasib and also by adagrasib, another drug approved a year ago against lung cancer. They are the only two authorized drugs that inhibit the KRAS protein. The new map also reveals another unknown Achilles heel: the so-called cavity 3. “Until now it was not known that this site had an allosteric effect and, therefore, pharmaceutical companies had not paid attention to it,” Escobedo points out.
It is the first time that it has been possible to create a complete map of the weak points – or allosterics – of a protein, according to the authors, led by the British biologist Ben Lehner and his Chinese colleague Chenchun Weng. Researchers emphasize that there are thousands of proteins associated with hundreds of human diseases, but very few have been controlled with drugs. “Most proteins do not have known allosteric sites,” lament the four scientists. Lehner and Faure, together with their colleagues Júlia Domingo and Pablo Baeza, launched on November 30 ALLOX, a company linked to the Barcelona Center for Genomic Regulation that will design new drugs directed at allosteric sites against cancer and other diseases. Like in Star Wars, scientists already have a plane and a weak point. Now they need to make a torpedo.
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