Scientists Spot Mechanism Behind Lung Cancer Drug Resistance

Adding another medication can solve the problem, researchers say

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By
HealthDay Reporter

THURSDAY, April 26, 2007 (HealthDay News) -- Scientists have discovered a key means by which some lung cancer tumors become resistant to drugs such as Iressa and Tarceva.

The finding could lead to better combination drug treatments, the researchers report.

"We wanted to find out why tumors become resistant to certain drugs," explained senior researcher Dr. Pasi A. Janne, an assistant professor of medicine at Harvard Medical School. "While patients respond to drugs like Iressa and Tarceva, the majority of patients become resistant to them. The cancers figure out a way to grow in the presence of these drugs."

His team reported its findings in the April 26 online edition of Science.

Doctors often resort to drugs such as Iressa (gefitinib) and Tarceva (erlotinib) to treat advanced non-small-cell lung cancer. These agents work by blocking epidermal growth factor receptor (EGFR), a molecule lying on the surface of cancer cells.

Tumors that respond to these EGFR inhibitors shrink rapidly and dramatically, but in time they can become resistant and start growing again.

In about half of the cases, a mutation in the EGFR gene interferes with the ability of the drug to bind to the receptor. Once this happens, these drugs cease to work.

However, in many other cases the cause of resistance remains unknown.

Investigating that issue, Janne's team experimented with lung cancer cells resistant to Iressa.

They found that a mutation in a second gene can also cause the drug to stop working. "We identified a single mutation in another gene that occurred in the drug-resistant cells," Janne said. "This is the MET oncogene. And we have a specific drug that targets this gene."

Analysis of samples from patients whose tumors became resistant after initially responding to Iressa showed that the MET mutation was present in samples from four of 18 patients.

"When we treated the resistant cells with a MET inhibitor, it completely restored the effectiveness of Iressa," Janne said. "We found the same MET mutation in about 20 percent of lung cancer patients."

This is a wholly new mechanism for lung cancer drug resistance, Janne said, and it is also "a mechanism that we can target with a specific drug. This is a potentially new and important therapy for these individuals." he said. According to Janne, similar mechanisms may also be at work in other cancers.

The Harvard group is working on ways to combine treatment with currently available EGFR inhibitors and MET inhibitors that are currently in clinical trials. They also want to study more drug-resistant samples, to get a better idea of how often this resistance mechanism occurs.

One expert views the finding as another indication of cancer's complexity.

"This shows the complexity of treating a rapidly changing tumor type," said Michael Melner, a scientific program director at the American Cancer Society. "The mutation of the MET gene is only one explanation out of many for the resistance of the tumors."

Drug combinations appear more and more necessary for treating many cancers, Melner added. "This is another study that points to things being more complex than we think they are. Clearly, combinations of drugs are going to be necessary to treat multiple cancer types. And this is just another indication of that," he said.

More information

For more information on lung cancer, visit the U.S. National Cancer Institute.

SOURCES: Pasi A. Janne, M.D., Ph.D., assistant professor, medicine, Harvard Medical School, Boston; Michael Melner, Ph.D., scientific program director, American Cancer Society, Atlanta; April 26, 2007, Science

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