Using data from the Human Genome Project, University scientists have identified genetic mutations linked to lung cancer in nonsmokers.
Clinicians at Memorial Sloan-Kettering Cancer Center are testing the possibility that tumors with the mutations may dramatically “melt away” when treated with a class of drugs known as kinase inhibitors.
“It’s early, but this could mean patients with these mutations could be successfully treated without having to go through chemotherapy and the much tougher side effects that brings into play,” said Richard K. Wilson, Ph.D., professor of genetics and director of the Genome Sequencing Center (GSC). “That would be huge.”
The study recently appeared in the Proceedings of the National Academy of Sciences.
Harold Varmus, M.D., senior investigator for the project and president of Memorial Sloan-Kettering, asked Wilson and his colleagues for help in learning more about the genetic basis of lung cancers in nonsmokers.
Lung cancer treatment frequently begins with surgical removal of tumors, so the Sloan-Kettering group was able to send more than 100 tumor samples to the University.
GSC scientists initially made plans to sequence several different genes in smokers and nonsmokers.
“As we were getting started on that, they let us know that preliminary evidence was starting to point toward the gene for epidermal growth factor receptor (EGFR) protein,” said Wilson, who also is an associate professor of molecular microbiology.
Found on the surface of many cell types, EGFR binds to another protein called epidermal growth factor, triggering DNA replication and cell division. Because of its links to growth, EGFR was identified in the 1980s as a potential oncogene, a gene that can cause cancer when mutated or abnormally activated.
In a comparison of the EGFR gene in smokers’ lung tumors and nonsmokers’ tumors, GSC researchers found mutations in 47 percent of nonsmokers, but only in 5 percent of smokers.
The mutations occur in a region of the protein known as the tyrosine kinase domain, which is involved in the protein’s signaling function. EGFR turns on growth by sending a signal to the nucleus, the central compartment of the cell where DNA is kept.
Researchers suspect the mutations jam this signal permanently into its “on” position.
Tumors with the mutations appear to be very vulnerable to the drugs Iressa and Tarceva.
“Doctors at Sloan-Kettering are giving these drugs to people with this mutation who have fairly late-stage lung tumors, and they’re getting extremely good responses,” Wilson said. “If we could use a test for these mutations to diagnose people early on, we might even be able to treat them before the point where they must have surgery.”
Wilson cautions there is still much to be learned about the mutations and their interactions with treatment. For example, there may be particular forms of the mutations that are much less sensitive to Iressa and Tarceva, and some tumors may be able to develop resistance to the drugs.
According to Wilson, scientists can start answering those questions with a combination of data from patients and from the Human Genome Project. He speculates this may one day help scientists identify similar genetic irregularities in lung tumors in smokers.
“There may not be any drug that we know of yet for blocking that alternative pathway in smokers, but just determining that pathway is there could be the first step toward designing something to stop it,” Wilson said.
“We’re going to see a lot more of these kinds of findings in the coming years, and data from the Human Genome Project and the high-throughput genetic sequencing technology we’ve built over the last decade are what will make them possible.”