( An international research team led by ...)New Mechanism Identified for Resistance to Targeted Lung Cancer Drugs,Health

An international research team, led by investigators from the Massachusetts General Hospital (MGH) Cancer Center and Dana-Farber Cancer Institute (DFCI), has found// a new way that some lung tumors become resistant to treatment with targeted therapy drugs like Iressa and Tarceva. Their report, which will appear in the journal Science and is receiving early online release, describes a totally new resistance mechanism that may apply to many types of cancer. It also suggests a treatment strategy for patients with these resistant tumors.

"We found that, for about 20 percent of patients with tumors that become resistant to Tarceva or Iressa, resistance is caused by the genetic activation of an oncogene that is not the normal target of the drug, which is something that has never been seen before," says Jeffrey Engelman, MD, PhD, scientific director of the MGH Center for Thoracic Cancers, the paper's lead author.

"Importantly, we also identified a potential new way to treat these resistant tumors with combination therapy directed against both protein targets," adds Pasi A. J?nne, MD, PhD, of the Lowe Center for Thoracic Oncology at DFCI, the study's senior author.

Drugs 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. They act by blocking the epidermal growth factor receptor (EGFR), a molecule on the surface of cancer cells. In 2004 research teams from MGH and DFCI found that only tumors in which the EGFR gene has been mutated in a way that magnifies the cells' response to the growth factor, a process that fuels tumor growth, were sensitive to treatment with these drugs.

Although tumors that respond to EGFR inhibitors do so rapidly and dramatically, eventually the tumors become resistant and resume growing. About half the time, a secondary mutation that interferes with the drugs' binding to the receptor develops within
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