Behind the Science

An ‘Achilles Heel’ in Common Cancer Gene Mutation

By Rachael Bieschke

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The protein K-Ras is the most commonly mutated oncogene in human cancers. Because of this notorious reputation, researchers have been trying, unsuccessfully, for three decades to develop a drug that might inhibit it. Targeting K-Ras has proved so elusive that the scientific community has dubbed it “undruggable” – a moniker that may now have to change thanks to some exciting research from the Howard Hughes Medical Institute (HHMI).

The researchers identified a “pocket” or binding site in K-Ras, and designed a chemical compound that effectively sits inside it, inhibiting its normal activity. This could open a new pathway to target a wide range of cancers with Ras mutations, which are typically aggressive and difficult to treat with standard therapies.

Ras proteins are small enzymes that transmit signals inside cells, playing an essential role in cell growth and survival. When the K-Ras gene is mutated, it causes more active signaling within your cells, potentially causing normal cells to become cancerous. K-Ras mutations are quite common and are found in 30 percent of all human tumors, including:

  • 90 percent of pancreatic cancers
  • 40 percent of colon cancers
  • 20 percent of non-small cell lung cancers

The development of new drugs or other therapies that might target K-Ras mutations could have a significant impact on cancer outcomes, which is why the National Cancer Institute recently announced it would be coordinating a $10-million Ras Project to develop new Ras-blocking ideas. The HHMI study, however, already shows great promise. Charles Sawyers, who was not part of the study, said:

“The potential clinical impact of a K-Ras inhibitor cannot be overstated—this is one of cancer’s holy grails … The Shokat team’s success, achieved by focusing on a single K-Ras mutant, could catalyze a new drug discovery strategy for the entire Ras inhibitor field. Their results suggest that Ras is not a single target but multiple targets. It is still early days, but one can begin to envision a collection of different Ras inhibitors, each customized to inhibit different Ras mutants.”

This finding is just the latest in novel gene therapies that could change the future of cancer treatment. Last year, researchers made a gene discovery that may help stop cancer cells from spreading, while other research has focused on new cancer drugs called CDK inhibitors, which work by blocking a genetic pathway for cellular growth, and have been described as a potential breakthrough treatment for hard-to-treat forms of breast cancer.


Howard Hughes Medical Institute