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When Stephen Fesik left the pharmaceutical industry to launch an academic drug-discovery laboratory, he drew up a wanted list of five of the most important cancer-causing proteins known to science. These proteins drive tumour growth but have proved to be a nightmare for drug developers: they are too smooth, too floppy or otherwise too finicky for drugs to bind to and block. In the parlance of the field, they are 'undruggable'.
One of the first culprits that Fesik added to his list was a protein family called Ras. For more than 30 years, it has been known that mutations in the genes that encode Ras proteins are among the most powerful cancer drivers. Ras mutations are found in some of the most aggressive and deadly cancers, including up to 25% of lung tumours and about 90% of pancreatic tumours. And for some advanced cancers, tumours with Ras mutations are associated with earlier deaths than tumours without them.

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Decades of research have yet to yield a drug that can safely curb Ras activity. Past failures have driven researchers from the field and forced pharmaceutical companies to abandon advanced projects. But Fesik's laboratory at Vanderbilt University in Nashville, Tennessee, and a handful of other teams have set their sights anew on the proteins. They are armed with improved technology and a better understanding of how Ras proteins work. Last year, the US National Cancer Institute launched the Ras Initiative, a US$10-million-a-year effort to find new ways to tackle Ras-driven cancers. And researchers are already uncovering compounds that, with tweaking, could eventually yield the first drugs to target Ras proteins.
Researchers are mindful that they still have many hurdles to jump. “You have to have a lot of respect for Ras,” says Troy Wilson, president of Wellspring Biosciences, a company in La Jolla, California, that launched in 2012 with its sights set on Ras. “It is not to be underestimated. But it's also one of the most important oncogenes in cancer.”
Advocates of this Ras renaissance say that any signs of success could provide lessons on how to target other important proteins that are deemed to be undruggable. Just because people assume Ras proteins are too difficult to target does not mean that scientists should give up, says Channing Der, a cancer researcher at the University of North Carolina at Chapel Hill. “Dogma is a moving target.”

High-hanging fruit

In 1982, Der's team was one of the first to show that mutations in human genes encoding Ras proteins can cause cancer1. This finding marked the culmination of a hunt for oncogenes — genes that can drive cancer — in the human genome. They had previously only been described in viruses and animal models.
The discovery laid the foundation for the modern cancer-research juggernaut, with its emphasis on tracking genetic mutations and mapping altered molecular pathways. It also prompted hopes of finding drugs that would target oncogenes and cure some cancers.
The following years were filled with discovery. It became clear that humans produce three highly similar Ras proteins and that these are activated when cells need to proliferate (to replace damaged tissue, for example). Signals from outside the cell switch Ras to an 'on' state, in which it is bound to a molecule called GTP. Cancer-causing forms of Ras proteins have a disabled 'off' switch and cannot properly process the GTP. So it seemed logical to search for drugs that could interfere with GTP binding to stop mutant Ras.
But as the understanding of Ras biochemistry grew, so too did a sense of pessimism. The family's affinity for GTP turned out to be extraordinarily high, and finding another compound that could block GTP's access seemed impossible. Ras proteins also work by interacting with other proteins, but small-molecule drugs that are able to get inside cells are often too small to cordon off the wide surface area usually involved in protein–protein interactions. (Antibodies can make excellent drugs and can mask a large area on their targets, but most do not penetrate cell membranes.)
Ras structures offered more reasons for concern. Drug developers look at a protein's shape to gauge the likelihood of finding a compound that will bind to a critical site. They like to see a protein with deep pockets that a drug can slip into and bind with multiple points of contact. However, Ras proteins are relatively smooth.
Twenty years ago, researchers thought they had the problem solved. To function, Ras proteins need to latch on to the inside of the cell membrane through a fatty tail. That tail is added by farnesyl transferase — an enzyme that is more amenable to drug targeting than Ras proteins. So the idea was to hobble Ras activity by finding drugs that inhibit farnesyl transferase.
At first, it looked like a winning strategy. Farnesyl transferase inhibitors damped down cell proliferation in mice and human cancer cells2. By the early 2000s, at least six pharmaceutical companies were racing to bring the drugs to market. Many abandoned other Ras-related projects because they thought the Ras problem was solved, says chemist Herbert Waldmann of the Max Planck Institute of Molecular Physiology in Dortmund, Germany. “The whole field took a deep breath and waited,” he says.
The wait ended with one of the biggest disappointments in pharmaceutical history. One by one, the drugs failed in human clinical trials. Der, who was still studying Ras at the time, says that the episode taught him, and everyone else, an important lesson about Ras biology.
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