Possible KRAS downstream target for pancreatic cancer therapy identified

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A protein called GSK-3 alpha may promote oncogenic KRAS function, according to first evidence in a new study. Inhibiting GSK-3 in a model of pancreatic tumors yielded a strong anti-tumor response, thus offering a potential therapeutic option.

While the mutated KRAS oncogene is associated with many cancers, it has not yet been successfully targeted by a therapeutic agent. This study is an effort to find another way to target the gene by blocking signals from another protein downstream.

“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 signaling. But how KRAS activates NF-kappa B has not been well understood. We have found a link,” said study senior author Albert S. Baldwin, PhD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.

GSK-3 has alpha and beta forms. The beta form, which has been studied previously, is considered a tumor suppressor. GSK-3 alpha was considered redundant to GSK-3 beta, but the research team found that GSK-3 alpha has a different function than GSK-3 beta. Their studies were done in mice with human pancreatic tumors.

"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. The study was published in Cancer Discovery (2013; doi: 10.1158/2159-8290.CD-12-0541).
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