The vulnerable cancer cell(ing short hairpin RNAs (shRNAs) -- singl...),Health

"We were looking at genes that we thought we could target easily with drugs," Gilliland said. "We looked for genes that when knocked down would confer lethality to cells that were KRAS-mutant, but not KRAS-wild-type." This approach is a particularly attractive concept in cancer research because normal cells don't have the same dependencies on these genes. "If you find a vulnerability conferred by another gene, you should, in theory, have a great therapeutic window because you're not going to affect normal cells," he said.

Gilliland's group began a collaboration with William C. Hahn at the RNAi Consortium at the Broad Institute to use the Broad's automated RNAi screening technology to assess about 5,000 shRNAs targeting about 1,000 human genes in a panel of eight human cancer cell lines. The shRNAs were carried in lentiviral vectors, which the researchers used to infect four cell lines carrying KRAS mutations and four lines carrying KRAS-wild-type genes.

At the top of the "hits" identified in the screen was the serine/threonine kinase, STK33, which Gilliland describes as a "totally new gene" in cancer research circles. "There are a couple of older papers describing STK33's genetic localization and exon structure, but otherwise nothing else is known about it."

That's about to change as Gilliland and his team begin to explore why STK33 represents a liability for KRAS-mutant cancer cells. Evidence presented in Cell shows that STK33 is not a part of the RAS signaling pathway, nor is it mutated in human cancer cell lines that were tested. Gilliland said his group's experiments indicate that STK33 is involved in induction of the cell death pathway in cancer c
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