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“The existing literature was equally compatible with either of those two models,” says Green. “So, we decided to do an unbiased test to determine which of these two models was correct.”
That test consisted of a mass screening using mouse cells engineered to have a mutated ras that was abnormally activated to silence Fas. One by one, the researchers switched off each of 28,000 genes in the mutant mouse cells. They were looking for any genes that, when switched off, blocked ras's silencing mechanism, freeing Fas to do its work. The screening identified 28 genes that were necessary for ras to silence Fas. The proteins encoded by these genes compose a pathway responsible for regulating a chain of events, beginning at the cell surface, where ras works, and leading into the nucleus, where Fas is silenced.
“The most surprising thing was the complexity of this pathway and its apparent nonredundancy,” says Green. “I might have predicted that an instructive pathway such as this would consist of a handful of genes, but certainly not twenty-eight components.”
Besides studying Fas silencing, the researchers also tested whether ras used the same house-of-cards pathway to silence other genes known to be suppressed in cancer cells. They found that most of the 28 genes were critical for ras to silence each of the five other genes tested. This broad dependence on the house-of-cards pathway means that drugs that target the pathway might well cut a wide, lethal swath through the aberrant machinery of ras-driven cancers.
Having found that the pathway was integral for ras's ability to silence genes, the researchers then asked whether any of the components were also required for ras to cause cancer. The team found that removing any one of several components abolished the ability of ras to induce tumor growth in mice. These results demonstrated that taking out a single participant in the house-of-cards pathway could bring down ras's ability to cause cancer. The findings have important therapeutic implications.
“We are not very good at curing cancer,” Green says. “Chemotherapeutic drugs currently in use are toxic to all dividing cells, which means that they have very broad side effects. Inhibitors of ras-mediated epigenetic silencing—which cause changes only within cancer cells—could represent important progress toward targeted therapies.”