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Cancer cells need normal, nonmutated genes to survive
Date:5/28/2009

hen you compare the DNA sequences of cancer cells with normal cells," says Luo.

So the team took a different approach to test their "non-oncogene addiction" hypothesis. They acquired two human cell lines, identical in every way except for onethe presence or absence of a Ras oncogene. Ras mutations are prevalent in many deadly cancers, and researchers have not been successful in developing drugs against the dangerous gene.

The team used molecules called shRNAs to interfere with the production of thousands of normal, healthy proteins in the two cell lines. They gave the cells time to divide and sifted through the data to determine which proteins were required for survival. (In the past, labs relied on large robots to complete these types of screens, but Elledge and others have refined the technology in an effort to make RNAi affordable and accessible. Luo conducted his genome-wide screen in test tubes without the aid of a robot.)

Despite their similarities, the two cell lines responded differently to a number of shRNAs. That is, normal cells tolerated low levels of a particular protein while cells with the Ras mutation perished. Luo validated 50 of these hits in a second pair of cell lines. Dozens of these represent brand new therapeutic targets.

"This opens the door to using a drug cocktail approach to treat tumors driven by Ras mutations," says Elledge, who is also an investigator with Howard Hughes Medical Institute. "We might be able to tinker with the levels of these proteins and cripple cancer cells without hurting normal cells in the body, though this needs to be tested in tumor models."

"This type of functional approach complements the physical mapping of cancer genomes, but provides a much more direct path to new anti-cancer drug targets," adds Luo. "The genes that are critical for maintaining the malignant state will really crystallize when we combine forces."


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Contact: Alyssa Kneller
communications@hms.harvard.edu
617-432-0442
Harvard Medical School
Source:Eurekalert

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