1 min readScientists Identify Possible KRAS Downstream Target for Pancreatic Cancer Therapy

Chapel Hill, NC – While the mutated KRAS oncogene is associated with many cancers, it has not yet been successfully targeted by a therapeutic agent. Scientists are trying to find another way to target the gene by blocking signals from another protein downstream.

A University of North Carolina School of Medicine team offers first evidence of the role of a protein called GSK-3 alpha in promoting oncogenic KRAS function. When the scientists inhibited GSK-3 in a model of pancreatic tumours, the team got a strong anti-tumour response, thus offering a potential therapeutic option.  Their findings are published in the June issue of the journal Cancer Discovery. 



Albert Baldwin, William Rand Kenan Professor of Biology, study senior author, and associate director of UNC Lineberger Comprehensive Cancer Center, says, “GSK-3 promotes activity of a protein called NF-kappa B. Our lab has been studying NF-kappa B for a number of years and has published that this protein is important in KRAS signalling.  But how KRAS activates NF-kappa B has not been well understood.  We have found a link.”



GKS-3 has alpha and beta forms. The beta form has been studied and is considered to be a tumour suppressor. GSK-3 alpha was considered to be redundant to GSK-3 beta. The research team studied GSK-3 alpha in mice with human pancreatic tumours and found through their experiments that its function is different from GSK-3 beta. 



“Our data suggest that GSK-alpha is really an onco-protein and that KRAS utilizes GSK-alpha to activate both NF-kappa B pathways, called canonical and noncanonical. This finding is important because GSK-3 alpha sits on top of the two pathways and inhibits them both, thus making it a viable therapeutic target. We are conducting further pharmacologic studies,” said Baldwin.

Publication: GSK-3α Promotes Oncogenic KRAS Function in Pancreatic Cancer via TAK1–TAB Stabilization and Regulation of Noncanonical NF-κB. Deepali Bang,  Willie Wilson, Meagan Ryan, Jen Jen Yeh, and Albert S. Baldwin. Cancer Discovery (Published Online First April 1, 2013): http://cancerdiscovery.aacrjournals.org/content/early/2013/05/21/2159-8290.CD-12-0541.abstract

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