Discovery of a new mutation in a gene associated with non-small cell lung cancer helps to explain how tumors become resistant to gefitinib and may allow development of new drugs that will be more effective, according to an article in the February 24th issue of the New England Journal of Medicine.

Non-small cell lung cancer accounts for approximately 85 percent of all lung cancer cases and is the leading cause of death from cancer in among American men and women.

Gefitinib, which blocks the receptor for epidermal growth factor protein (EGFR) to suppress growth and spread of malignant cells, was approved by the U.S. Food and Drug Administration as a treatment for non-small cell lung cancer in 2003.
Clinical applications drug initially yielded very good results, with approximately 10 percent of patients experiencing complete remission of their disease. 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 senior author Balazs Halmos, MD. To determine if this was indeed the case, Halmos identified a 71-year-old patient with advanced disease whom he had been treating 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 receptor gene, which was causing cancer cells to become resistant to the drug, Halmos, together with the study’s corresponding author Daniel Tenen, MD, and Susumu Kobayashi, MD, PhD, obtained a second biopsy of the tumor and resequenced the receptor’s 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 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,” explained Tenen. “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.” 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,” said 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.”