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Second Gene Mutation Explains Lung Cancer Drug Resistance

Two teams of researchers arrive at similar finding

WEDNESDAY, Feb. 23, 2005 (HealthDay News) -- A second gene mutation explains why some lung cancer tumors become resistant to treatment with new cancer drugs meant to disrupt a molecular target that helps tumors grow, two separate research teams report.

Researchers from Beth Israel Deaconess Medical Center in Boston detail their findings in the Feb. 24 issue of The New England Journal of Medicine, and researchers from Memorial Sloan-Kettering Cancer Center in New York City outline their research in the Feb. 22 issue of PLoS Medicine.

The Sloan-Kettering researchers reported on six patients who had received treatment with either Iressa (gefitinib) or Tarceva (erlotinib), both new cancer drugs. The Beth Israel team reported on one patient who stopped responding to Iressa. All patients had non-small cell lung cancer, which accounts for about 87 percent of all lung cancers, according to the American Cancer Society.

Both drugs are relatively new to the market. Iressa was approved for use against lung cancer by the U.S. Food and Drug Administration in May 2003 and Tarceva was approved in November 2004.

Researchers reported last year that another gene mutation in these patients predicts which cancers will initially respond to the drugs, said Dr. William Pao, a Sloan-Kettering researcher and co-author of the study in PloS Medicine.

Researchers testing Iressa and Tarceva were initially puzzled, he said, as to why they worked in only about 9 percent or 10 percent of U.S. patients with lung cancers.

"For a long time, it was unknown why they only worked in a certain percentage," he said. When researchers looked more closely, he said, they found that the drugs worked best on adenocarcinomas, one of three types of non-small cell lung cancers, and on people who had never smoked.

Then, he said, "a number of groups, including ours, last year found there are mutations in the EGFR gene (epidermal growth factor receptor) that are associated with a [treatment] response. If you have that mutation, it is a good thing."

However, the more recent discovery found that the tumor stops responding if and when a secondary mutation in the same gene develops. "Three out of six patients [reported in the PLoS study] who had their tumor come back had this secondary mutation," Pao said.

In the Beth Israel study, researchers described the case of a 71-year-old man with advanced non-small cell lung cancer who relapsed on Iressa therapy following two years of remission.

That team, too, found the relapse was due to another mutation in the EGFR gene, which was causing the cancer cells to become resistant to Iressa. The Boston researchers found that insertion of the mutation into test cells made them resistant to Iressa in the lab.

What experts speculate is happening, Pao said, is that the drugs give cancer cells with the second mutation a growth advantage.

Lung cancer is the leading cause of cancer death for both genders, according to the cancer society. Besides adenocarcinomas, non-small cell lung cancers include squamous cell cancers, usually linked to smoking, and large cell undifferentiated cancer. In 2005, experts estimate that 172,000 new cases of lung cancer will be diagnosed in the United States, and about 163,000 people will die of the disease. About eight out of 10 people diagnosed with lung cancer die within two years of diagnosis.

The new genetic discovery is no surprise, said Dr. Herman Kattlove, medical editor for the cancer society and a medical oncologist.

"This is totally expected," he said. "We have seen the same thing with Gleevec." Researchers have discovered resistance can develop with this drug, which is another targeted therapy. Gleevec has been very successful in treating chronic myelogenous leukemia (CML) and other cancers, but experts have already designed second-line drugs to overcome the resistance.

"Cancer cells are very active in changing their nature -- that is why they are cancer cells," Kattlove said.

Next, Pao said, researchers will try to do what experts did with the Gleevec problem -- identify new drugs that might help overcome resistance. In fact, the Boston team of researchers say they have already achieved encouraging results in studies aimed at finding just that type of secondary agent.

More information

To learn more about lung cancer, visit the American Cancer Society.

SOURCES: William Pao, M.D., Ph.D., research fellow, Memorial Sloan-Kettering Cancer Center, New York City; Herman Kattlove, M.D., medical oncologist and medical editor, American Cancer Society, Los Angeles; Feb. 24, 2005, New England Journal of Medicine; Feb. 22, 2005, PLoS Medicine
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