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

Findings help explain how cancer cells develop resistance to gefitinib

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 Halmos, MD, a physician-scientist formerly at BIDMC and presently with the Ireland Cancer Center, University Hospitals of Cleveland. To detemine 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 another 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 gefitinib’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. “Our preliminary results have yielded encouraging findings, pointing towards drugs that might bypass this method of resistance,” says Johnson. “We’re now in the process of planning clinical studies to test novel EGFR inhibitor compounds in lung-cancer patients whose tumors have become resistant to gefitinib.”

The results may also lead to new diagnostic methods.

“I believe that findings like these will hasten the use of molecular oncology for everyday practice,” says Tenen. “Analogous to the way that antibiotic and antiviral regimens might be selected today based on the results of microbiological testing, I can certainly envision a time in the future when molecular monitoring for mutations and drug regimens will be adjusted based on these results.”

In addition to Halmos, Tenen, Kobayashi and Johnson, study coauthors include BIDMC investigators Olivier Kocher, MD, PhD, and Tajhal Dayaram, BA; and Dana-Farber Cancer Institute investigators Titus Boggon, PhD, Michael Eck, MD, PhD, Pasi Janne, MD, PhD, and Matthew Meyerson, MD, PhD.