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Study identifies mechanism of resistance to targeted therapy in lung cancer patients

A new study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) identifies a second mutation in a gene associated with non-small-cell lung cancer (NSCLC), a discovery that helps to explain why NSCLC tumors become resistant to treatment with the cancer therapy gefitinib (Iressa).

The findings, which are reported in the February 24, 2005 issue of The New England Journal of Medicine (NEJM), could help lead to the development of second-generation inhibitor drugs to treat NSCLC, which accounts for approximately 85 percent of all lung cancer cases and is the leading cause of death from cancer in the U.S. among both men and women.

One of a new generation of cancer therapies that work by disrupting the specific molecular target responsible for stimulating tumor growth, gefitinib acts on the receptor for the epidermal growth factor protein (EGFR) to halt the spread of cancer cells. In 2003, it was approved by the U.S. Food and Drug Administration as a treatment for NSCLC.

Clinical applications of the new drug initially yielded very good results, with approximately 10 percent of patients experiencing complete remission of their disease. Two separate studies published last year in NEJM and Science offered an explanation for how this was happening, suggesting that a mutation in the EGFR gene of these individuals was causing their cancer cells to produce abnormal versions of growth signals called tyrosine kinases. Among these patients, gefitinib works by snugly fitting into the activating pocket of the protein like a key into a keyhole, blocking the growth signals and thereby depriving the cancer cells of the stimuli they need to survive and proliferate.

However, in spite of the therapy's initial success, patients inevitably suffered a relapse and their tumors started to grow again.

"It appeared that the tumors in these patients had found a way to bypass the effects of gefitinib," explains the study's last author Balazs
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Contact: Bonnie Prescott
bprescot@bidmc.harvard.edu
617-667-7306
Beth Israel Deaconess Medical Center
23-Feb-2005


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