Molecular ‘brake’ stifles human lung cancer

Scientists at the Salk Institute have uncovered a molecule whose mutation leads to the aggressive growth of a common and deadly type of lung cancer in humans.

This enzyme, called EphA2, normally polices a gene responsible for tissue growth. But when EphA2 is mutated, the Salk team discovered, cellular systems can run amok and quickly develop tumours. The new work suggests that EphA2 could be a new target for a subset of lung cancer, which affects non-smokers as well as smokers, and is the leading cause of cancer-related deaths worldwide.

 “Sometimes there are hundreds of mutations in the genes of a patient’s tumors, but you don’t know whether they are drivers of the disease or by-products,” says senior author Inder Verma, professor of genetics and holder of Salk’s Irwin and Joan Jacobs Chair in Exemplary Life Science. “We found a new way by which to identify cancer suppressor genes and understand how they could be targeted for therapies.”

Two gene mutations in particular are known to spur the growth of human tumours: KRAS and p53. Though both genes have been heavily studied, they are difficult to therapeutically target, so the Salk team decided to look at genes that might police KRAS and p53 instead.

The researchers narrowed in on the 4,700 genes in the human genome related to cellular signalling–specifically, genes that have the ability to tamp down cell growth and proliferation. Then the team adapted a genetic screening technique to quickly and efficiently test the effect of these thousands of genes on tumour development. In animal models, the Salk team found that 16 of these cell-signalling genes produced molecules that had a significant effect on KRAS- and p53-related tumours.

Of these 16 molecules, one especially stood out: the EphA2 enzyme, originally discovered in the lab of another Salk scientist, Tony Hunter. Previously, EphA2’s significance in lung cancer was unclear, but the team discovered that its absence let KRAS-associated tumours grow much more aggressively.

“With a mutation in KRAS, a tumour forms in 300 days. But without EphA2, the KRAS mutation leads to tumours in half the time, 120 to 150 days,” says Verma, who is also an American Cancer Society Professor of Molecular Biology. “This molecule EphA2 is having a huge effect on restraining cancer growth when KRAS is mutated.” Mutated KRAS is a common culprit in approximately 10 to 20 percent of all cancers, particularly colon cancer and human lung cancer.

 “Since activating EphA2 led to the suppression of both cell signalling and cell proliferation, we believe that the enzyme might serve as a potential drug target in KRAS-dependent lung adenocarcinoma,” says Narayana Yeddula, a Salk research associate and first author of the paper. Salk Institute for Biological Studies