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 get around the growing problem of resistance to targeted therapy drugs like Iressa and Tarceva. In a report to appear in Proceedings of the National Academy of Science, researchers from Massachusetts General Hospital (MGH) Cancer Center and colleagues from Wyeth Pharmaceuticals research division describe finding how drugs called irreversible EGFR inhibitors apparently avoid resistance and may offer patients longer term remission. The study has received early online release on the PNAS website.

"These irreversible inhibitors form an unbreakable bond with the EGFR molecule," says Daniel Haber, MD, PhD, 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." The researchers also discovered a new mechanism underlying the development of resistance, one which the new drugs may be able to avoid.

EGFR inhibitors, like Iressa (gefitinib) and Tarceva (erlotinib), are used to treat advanced non-small-cell lung cancer (NSCLC), the leading cause of cancer deaths in the U.S. In 2004 MGH researchers found that a particular set of mutations in the EGFR molecule could identify patients whose tumors would respond to Iressa, which early clinical trials indicated was effective in less than 15 percent of patients. The identified mutations magnified the cells' response to growth factor, fueling tumor growth, but they also increased tumors' sensitivity to Iressa. Subsequent research found that similar mutations were associated with sensitivity to Tarceva.

Although results for those patients who did respond to these EGFR inhibitors were often rapid and dramatic, they were also short lived, lasting for an average of 6 to 8 months. Researchers at several centers attributed this resistance

Contact: Sue McGreevey
Massachusetts General Hospital

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