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For cancer cells, genetics alone is poor indicator for drug response
Date:4/12/2009

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In order to investigate this disparate behavior among cells, graduate student Sabrina Spencer and postdoctoral researcher Suzanne Gaudet, both in Sorger's lab, looked at a molecule called TRAIL, a protein that causes cells to, literally, commit suicidea process scientists call apoptosis. While TRAIL is a natural cell product, drug makers have been investigating ways to harness its power so that it can directly target cancer cells.

While TRAIL continues to be a promising drug candidate, its success rate isn't 100 percent, and the researchers wanted to figure out why.

The researchers took both cancerous and non-cancerous cells and exposed them to varying doses of TRAIL. Although these cell lines were known to be vulnerable to the molecule, a fraction always managed to survive.

The researchers noticed that when this outlier group was isolated and once again exposed to TRAIL, the cells and their immediate progeny continued to remain highly resistant for a short time. An immediate explanation might be that this group had developed some sort of genetic defense. However, when this new "resistant" group was given several days to reproduce, the pattern soon reset to the original: 90 percent died, ten percent survived.

"We knew that there were clearly factors at work here that were not genetic," says Spencer. "Genetic resistance would remain uniform in subsequent generations. But the factors at work here were clearly more dynamic."

Using a variety of imaging techniques, the researchers soon discovered that even though these cells were genetically identical the same cell in the same tissue doing the same thing, the actual numbers of proteins in each cell varied. Specifically, proteins involved in the cell-suicide mechanism triggered by TRAIL were affected. These protein levels altered the dynamics of the entire mechanism, sometimes making cells, for all intents and purposes, immune to TRAIL. While these protein levels were
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Contact: David Cameron
david_cameron@hms.harvard.edu
617-432-0441
Harvard Medical School
Source:Eurekalert

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