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Targeted therapy triggers complex mechanism of resistance
Date:9/21/2010

Washington, DC In order for targeted therapies against cancer to be effective, scientists need to understand upfront what related proteins in a signaling "network" makes a cancer cell resistant to a drug and selectively target them as well, say researchers at Georgetown Lombardi Comprehensive Cancer Center and Fox Chase Cancer Center.

In the September 21 issue of Science Signaling, the investigators discuss how cancer cells activate a network of pro-growth proteins that can bypass a molecule being therapeutically targeted. The researchers specifically found that many different genes were involved in rescuing cancer cells from treatment by different FDA-approved drugs that are designed to shut down the epidermal growth factor receptor (EGFR) a major driver of cancer and a target of many new therapies.

This evolutionary pressure to survive is the essence of drug resistance, and the only way to treat cancer in the face of such resistance is to also disarm some of those key "rescue" genes and proteins, says study co-author Louis Weiner, MD, director of Lombardi.

"We need to be thinking about targeting a biological network, not just a single molecule," says Weiner. "The field of targeted therapy has focused enormously on the target, less on the target's signaling pathway, and almost never on the network in which this signaling pathway is embedded. That needs to change."

He adds that the study demonstrates why targeted therapies don't work at all in many people, and function for only a short time in those who do initially respond.

To understand that, Weiner describes the EGFR signaling network as one that has dense connections among signaling proteins, feedback signaling loops, and a tendency toward protective redundancy provided by proteins that have overlapping functions.

"So any time you put pressure on cells and their dynamic signaling networks, you are inevitably challenging them to get around the problem they are experie
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Contact: Karen Mallet
km463@georgetown.edu
215-514-9751
Georgetown University Medical Center
Source:Eurekalert

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