Gene mutations predict which lung cancers will respond...( ein in eight of nine patients that had ...),Health

ein in eight of nine patients that had responded to Iressa, but no EGFR mutations were seen in tumors from seven patients who did not respond. In addition, many of the patients whose tumors responded to Iressa were of a subtype of NSCLC called bronchoalveolar cancer. Subsequently the researchers analyzed samples from 25 other NSCLC patients who had not been treated with Iressa. Two of those samples had mutations identical to ones found in Iressa-responding patients, and they were both bronchoalveolar tumors. Many samples from several other types of cancer were also studied, but none had similar EGFR mutations, indicating that they only are important in a particular subset of cancers.

To determine the effect of these mutations, the MGH team developed cultures of cells expressing two of the mutated receptor proteins. Compared with cells expressing the normal receptor, those with mutant EGFR responded much more powerfully to addition of growth factor, with a two- to three-fold increase in activation. In addition, receptor activation persisted six times longer in the mutant receptors than in cells with normal receptors.

Since most of the mutations identified in this study affect the area of the receptor targeted by Iressa, the researchers measured receptor activation in cells treated with various doses of the drug. They found that the mutated receptors were 10 times more sensitive to being inhibited by Iressa than were normal receptors.

"Understanding these mutations has helped us define the molecular basis of a type of lung cancer that relies on a particular signalling pathway which can be blocked," says Haber, a professor of Medicine at Harvard Medical School (HMS). "In addition, these mutations are unprecedented in that they increase proliferation of tumor cells while simultaneously making them more sensitive to drug treatment."

Thomas Lynch, MD, director of the MGH Thoracic Oncology Center and a co-lead author of the NEJM paper
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Contact: Sue McGreevey
smcgreevey@partners.org
617-724-2764
Massachusetts General Hospital
29-Apr-2004

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