CLEVELAND - A new study, published in the Feb. 24, 2005, issue of The New England Journal of Medicine, helps to explain why non-small-cell lung cancer (NSCLC) tumors become resistant to the cancer therapy gefitinib (Iressa).

Researchers at Beth Israel Deaconess Medical Center in Boston and the Ireland Cancer Center at University Hospitals of Cleveland say their discovery of a second mutation in a gene already associated with NSCLC could trigger the development of 'inhibitor' drugs to treat NSCLC.  This type of cancer accounts for approximately 85 percent of all lung cancer cases and is the leading cause of death from cancer in the U.S.

"It appeared that the tumors in these patients had found a way to bypass the effects of gefitinib," explains Balazs Halmos, MD, a physician-scientist formerly at BIDMC and now at the Ireland Cancer Center, University Hospitals of Cleveland. Dr. Halmos is one of the study's authors.

Gefitinib is one of a new generation of cancer therapies that work by disrupting the specific molecular target responsible for stimulating tumor growth. The drug targets the receptor for the epidermal growth factor protein (EGFR) to halt the spread of cancer cells. The U.S. Food and Drug Administration approved gefinitib as a treatment for NSCLC in 2003.

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 proteins 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 of their disease. To determine if this was indeed the case, Halmos identified a 71-year-old patient with advanced NSCLC whom he had been treating at BIDMC, and who had recently relapsed after two years of complete remission while undergoing gefitinib therapy.

Hypothesizing that the relapse may have been due to an acquired second mutation in the EGFR gene which was causing cancer cells to become resistant to the drug, Halmos, together with the study's corresponding author Daniel Tenen, MD, a molecular biologist in the Division of Hematology/Oncology at BIDMC, and Susumu Kobayashi, MD, PhD, a physician-scientist in Tenen's laboratory, obtained a second biopsy of the tumor and resequenced the EGFR tyrosine kinase domain.

Their studies confirmed the existence of a second mutation, and insertion of this mutation into test cells rendered them resistant to gefitinib in vitro. Further analysis revealed that the newly identified mutation was altering the protein's drug-binding pocket and thereby changing the 'keyhole' so that the 'key' - gefitinib - no longer fit.

"The development of a second mutation suggests that the tumor cells remain dependent on an active EGFR pathway for their proliferation," explains Tenen, who is also a Professor of Medicine at Harvard Medical School. "This mirrors the situation that developed over the past few years among patients with chronic myeloid leukemia and gastrointestinal stromal tumors who were being treated with imatinib [Gleevec]." In those cases, he adds, the identification of mechanisms of resistance helped lead to the development of second-generation inhibitor drugs now being clinically tested.

And in fact, according to study coauthor Bruce Johnson, MD, Director of the Dana-Farber/Harvard Cancer Center Lung Program, clinical investigators are already moving in this direction.

"We're in the process of planning clinical studies to test novel EGFR inhibitor compounds in lung-cancer patients whose tumors have become resistant to gefitinib," says Johnson, adding that these findings could also lead to new diagnostic techniques.

This study was funded by grants from the National Institutes of Health and the Dana-Farber/Harvard Cancer Center Lung Cancer SPORE Program.

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By: UHHS News