May 20, 2005

New class of drugs may treat lung tumors resistant to Iressa and Tarceva

A new class of drugs that block the epidermal growth factor receptor (EGFR) on lung cancer cells may avoid the problem of resistance to the targeted therapy drugs Iressa and Tarceva. In a report issued on the Proceedings of the National Academy of Science (PNAS) website, researchers from the MGH Cancer Center describe finding how drugs called irreversible EGFR inhibitors apparently avoid resistance and may offer patients longer term remission.

In 2004, MGH researchers found that particular mutations in the EGFR molecule identified patients whose tumors would respond to drugs like Iressa. But although improvement for those patients is often rapid and dramatic, it lasts for only an average of six to eight months. In the current study, the MGH-based team confirmed that some resistance is associated with a previously observed second EGFR mutation, but they also showed that disruption of the way the molecule is handled in the cell could be behind most resistance. Most importantly, they found that tumor cells with either type of resistance continued to be sensitive to the new class of irreversible EGFR inhibitors. One of those drugs is already in the process of clinical testing, and members of the MGH team are planning to conduct a clinical trial for appropriate lung cancer patients.

“These irreversible inhibitors form an unbreakable bond with the EGFR molecule,” says Daniel Haber, MD, PhD, (shown above) director of the MGH Cancer Center and senior author of the PNAS paper. “The initial group of EGFR inhibitors can fall off the receptor, but once the irreversible inhibitors bind, the receptor is permanently out of commission.”

Eunice Kwak, MD, PhD; Raffaella Sordella, PhD; Daphne Bell, PhD; and Nadia Godin-Heymann, PhD, are co-first authors of the PNAS study. Additional MGH
co-authors are Ross Okimoto, Brian Brannigan, Patricia Harris, David Driscoll, Panos Fidias, MD, Thomas Lynch, MD, Sreenath Sharma, PhD, Kurt Isselbacher, MD, and Jeffrey Settleman, PhD.