Researchers discover the weak points of the protein that causes one in 10 cancers

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 heel. 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 key to the new advance is allosterism, a phenomenon considered “the second secret of life,” by French biologist Jacques Monod, who won the 1965 Nobel Prize in Medicine for discovering it. DNA is the first secret. Monod realized that proteins had some kind of hidden buttons that changed their function. Finding these switches 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 atoms of carbon atoms, 1,516 of hydrogen, 260 of nitrogen, 291 of oxygen and 10 of sulfur. It is a chemical giant that has been impregnable for decades.

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.

The researchers 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, which is targeted by sotorasib and adagrasib, another drug against lung cancer that was approved last year. 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, as a result, pharmaceutical companies had not paid attention to it,” says Escobedo.

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 point out that there are thousands of proteins linked to hundreds of human diseases, but very few have been controlled with drugs. “Most proteins do not have known allosteric sites,” say the scientists. Lehner and Faure, together with their colleagues Júlia Domingo and Pablo Baeza, launched ALLOX on November 30, a company linked to the Barcelona Center for Genomic Regulation that will design new drugs targeting allosteric sites against cancer and other diseases. As in Star Wars, scientists already have a blueprint and a weak point. Now they need to make a weapon.

Biochemist Mariano Barbacid was one of the main researchers involved in the discovery of KRAS — the first human gene linked to cancer — more than four decades ago. The researcher recalls that it was three decades before Kevan Shokat, a chemist of Iranian origin working at the University of California in San Francisco, found “a small cleft” in the KRAS protein in 2013. This discovery paved the way for the development of the first selective inhibitors, sotorasib and adagrasib. “Since then, a whole series of inhibitors against the different mutated forms of KRAS have been synthesized. Unfortunately, the therapeutic activity of these molecules has not been as effective as expected,” says Barbacid, of the Spanish National Cancer Research Center (CNIO) in Madrid.

Barbacid highlights research from oncologist Luis Paz-Ares and his team at Madrid’s 12 de Octubre hospital, which showed in February that a lung cancer patient who is treated with sotorasib has similar rates of survival to one given classic chemotherapy, although they have less toxicity and experience a better quality of life. “The therapeutic response of pancreatic tumors, at least for the moment, is even more limited. Therefore, although the availability of these drugs is a very important milestone in molecular oncology after 40 years of effort, it is also a humbling experience that tells us that further research will be needed to obtain more and better inhibitors,” adds Barbacid, who was not involved in the new study.

Barbacid published research in March that showed that eliminating the KRAS gene in genetically modified mice resulted in the total disappearance of their tumors. “Bearing in mind that experimental results are not always reproduced in a clinical setting, it is quite possible that significantly more potent KRAS inhibitors than the current ones could have similar effects in patients. Studies such as the one published by this group of researchers open up a very important and hopeful roadmap to achieve this goal,” he says.

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