Cancer Drug's Fickle Nature Explained

Lazarus response. New research explains why Iressa clears lung tumors only in a minority of patients.

Lung cancer is the leading cause of cancer death, killing roughly 160,000 people in the United States every year. Recently, however, a new drug called gefitinib (Iressa) has given patients a glimmer of hope, while presenting a puzzle: Iressa shrinks tumors in only about 10% of the patients who take it, but when it does work, clinicians say, it works amazingly well. New research provides an explanation--and may lead to better treatments for lung cancer and perhaps for other cancers as well.

In a paper published online by Science on 29 April, researchers at Harvard's Dana-Farber Cancer Institute in Boston report that the tumors of patients who respond to Iressa carry mutations in one of their proteins, the receptor through which epidermal growth factor (EGF) sparks cell growth. In addition, Daniel Haber and his colleagues at Massachusetts General Hospital in Boston report very similar findings in a paper that will appear in the 20 May issue of The New England Journal of Medicine and is also being published online this week. The work suggests that the mutations drive lung cancer growth and that Iressa--which inhibits EGF receptor activity--checks that growth.

The EGF receptor is a kinase, an enzyme that regulates proteins by attaching phosphate groups to them. Both groups found that the mutations cluster near the catalytically active site of the receptor kinase, which is also where Iressa binds. Experiments on cultured cells by Haber and his colleagues showed that the mutant receptors “signal at a higher level in response to EGF and don't turn off.” Thus, the mutations may confer a growth advantage on tumor cells even while making them much more susceptible to Iressa.If the mutated EGF receptor really does predict how well Iressa is likely to work, "it would be the single most important finding in lung cancer genetics ever,” enthuses lung cancer specialist David Carbone of Vanderbilt University School of Medicine. Clinicians should now be able to screen newly diagnosed lung cancer patients to see if their tumors carry the EGF receptor mutations and are thus good candidates for Iressa therapy. Patients might then take the drug immediately in hopes of warding off lethal tumor growth, instead of very late in the disease as has usually been the case so far. Although the new findings are good news for some lung cancer patients, they are in some ways a mixed bag. Iressa may well have to be taken for life--at a cost of $2000 to $3000 per month. And the market for Iressa seems likely to narrow--not what manufacturers want to hear. On the bright side, however, EGF receptors on other kinds of tumor cells might carry similar mutations, in which case Iressa might be used to treat them, too.

Related sites
The Sciencexpress paper
The NEJM paper
Lung cancer resources from the National Cancer Institute

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