Study finds mechanism for drug resistence

Posted by rob on February 27, 2005 under Uncategorized | Be the First to Comment

Study finds mechanism for drug resistence

Source: (cancerfacts.com)

Friday, February 25, 2005

BOSTON – Feb. 25, 2005 – A new study shows that a second mutation in a gene associated with non-small-cell lung cancer (NSCLC) helps to explain how the tumors become resistant to new generation drugs like gefitinib (Iressa®).

Led by Dr. Balazs Halmos, a physician-scientist formerly at Beth Israel Deaconess Medical Center and now with the University Hospitals of Cleveland, and Dr. Daniel Tenen, a molecular biologist at Beth Israel, the researchers found that the non-small cell lung tumors appear to develop a second mutation that allows them to evade the action of the new generation drugs.

“The development of a second mutation suggests that the tumor cells remain dependent on an active EGFR pathway for their proliferation,” Tenen said in a prepared statement. “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®).”

The new drugs are designed to target a specific gene mutation that produces an abnormal epidermal growth factor protein (EGFR), which allows the tumor to grow unchecked. Gleevec is a similarly designed drug that has been very effective in the treatment of a certain type of leukemia. In some people, however, Gleevec seems to gradually lose effectiveness.

In those cases, says Tenen, who is also a professor of medicine at Harvard Medical School, the identification of mechanisms of resistance helped lead to the development of second-generation inhibitor drugs. The new study appears in the Feb. 24, 2005 issue of The New England Journal of Medicine.

Gefitinib is one of a new generation of cancer drugs that work by disrupting a specific molecular target within the cell. In this case the abnormal protein responsible for stimulating tumor growth. Gefitinib acts on the receptor for the epidermal growth factor protein (EGFR) to halt the proliferation of cancer cells. In 2003, it was approved by the U.S. FDA as a treatment for non-small cell lung cancer.

Clinical applications of the new drug initially yielded very encouraging results, with approximately 10 percent of patients experiencing complete remissions. Unfortunately, the remissions were not long-lived and the cancer returned.

Hypothesizing that the relapses may have been due to another mutation in the EGFR gene that was causing cancer cells to become resistant to the drug, the researchers obtained a second tissue sample of the tumor from patients treated with gefitinib and resequenced, or remapped, the genetic sequence of the EGFR gene.

Their studies confirmed the existence of a second mutation, and insertion of this mutation into cells in test tubes made them resistant to gefitinib. Further analysis showed that the newly identified mutation was altering gefitinib’s binding pocket and thereby changing the “keyhole” so that the “key” in gefitinib no longer fit.

According to study coauthor Dr. Bruce Johnson, director of the Dana-Farber/Harvard Cancer Center Lung Program, clinical investigators are already moving to develop a new drug designed to overcome this second mutation.

“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.”

cancerfacts.com.