the EGFR gene. A new group of so-called irreversible EGFR inhibitors that permanently bind to the protein are currently being tested in clinical trials. But what leads to other cases of resistance has been unknown, and the current study was designed to discover additional mechanisms.

To do so, the investigators modeled in a laboratory setting what happens in lung cancer patients; they used a line of NSCLC cells with the sensitizing EGFR mutation and created a cell line resistant to treatment with Iressa. In a number of experiments comparing the resistant line with still-sensitive cells, they focused on the cell signalling pathway controlled by EGFR. In earlier research, Engelman and colleagues had found that the growth signal that starts with EGFR works through a related protein called ERBB3.

The current study showed that, in some of the resistant cells, ERBB3 is activated by amplification of a different oncogene called MET, in essence bypassing the blockage of EGFR. Analysis of samples from patients whose tumors became resistant after initially responding to Iressa revealed that MET was amplified in resistant samples from 4 of 18 patients. Although treating resistant cell lines with either Iressa or a MET inhibitor did not stop tumor growth, treatment with both agents did induce cell death.

"This method of reactivating the EGFR signalling pathway with MET may be a common resistance mechanism in other therapies that target receptors of the ERBB family, which are used against breast cancer, colon cancer, head and neck cancer, and the brain tumor glioblastoma multiforme," says J?nne, who is an assistant professor of Medicine at Harvard Medical School (HMS). Engelman is an HMS instructor of Medicine.

"Our results suggest that, when patients' tumors become resistant, repeat biopsies to identify which resistance mechanism is involved will be critical and could help us develop effective therapies for those resistant tumors,
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