May 4, 2007

Lung cancer drug resistance finding

Investigators from the MGH Cancer Center and Dana-Farber Cancer Institute (DFCI) have found a new way some lung tumors become resistant to targeted therapy drugs like Iressa and Tarceva. Their report, which will appear in the journal Science and has been released online, describes a totally new resistance mechanism and suggests a treatment strategy for patients with these resistant tumors. "We found that, for 20 percent of patients, resistance to Tarceva or Iressa is caused by the genetic activation of an oncogene that is not the normal target of the drugs, something that has never been seen before," says Jeffrey Engelman, MD, PhD, scientific director of the MGH Center for Thoracic Cancers and the paper's lead author.

Iressa and Tarceva are used to treat advanced non-small-cell lung cancer, the leading cause of cancer deaths in the United States. In 2004, research teams from the MGH and DFCI found that only tumors in which the gene for EGFR, the drugs' target protein, is mutated in a particular way were sensitive to treatment with these drugs. Those tumors respond to targeted drugs rapidly and dramatically, but eventually they become resistant and resume growing. Half of the time, a secondary mutation interferes with the drugs' binding to EGFR, but what leads to other cases of resistance has been unknown.

In the current study the MGH/DFCI research team discovered that, in some resistant cells, the signalling pathway controlled by EGFR is reactivated by a different oncogene called MET, bypassing the blockage of EGFR. They also found that treating those tumor cells with both Iressa and an MET inhibitor led to cell death, suggesting that a combination treatment may effectively treat resistant tumors, something they hope to test in a future clinical trial.