Drugs Inhibiting the KRAS Oncogene Suppress Growth of Pancreatic Tumors in Mouse Xenograft Model

Drugs that inhibit the activity of the enzyme GSK-3 alpha (glycogen synthase kinase 3 alpha) strongly suppress growth of human pancreatic tumor xenografts in mice as well as down regulate certain oncogenic NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) target genes.

GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways. In mammals, GSK-3 is encoded by two known genes, GSK-3 alpha and GSK-3 beta. GSK-3 has recently been the subject of intense research because it has been implicated in a number of diseases, including type II diabetes, Alzheimer's disease, inflammation, cancer, and bipolar disorder.

Investigators at the University of North Carolina (Chapel Hill, USA) have found that in pancreatic cancer cells GSK-3 alpha is upregulated by mutant KRAS (Kirsten rat sarcoma viral oncogene). The KRAS gene performs an essential function in normal tissue signaling, and its mutation is an essential step in the development of many cancers. A single amino acid substitution is responsible for the activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, and colorectal carcinoma.

In a paper published in the April 1, 2013, online edition of the journal Cancer Discovery, the investigators reported that GSK-3 alpha was required for promoting critical NF-kappaB signaling in pancreatic cancer cells. The transcription factors of the NF-kappaB family are upregulated in many human cancers. NF-kappaB has roles in all stages of carcinogenesis or cancer progression, including protection from cell death, increase of cell proliferation, cell motility and metastasis, tumor inflammation, and angiogenesis. In addition, tumor cells often acquire resistance to anticancer drugs by upregulating NF-kappaB signaling.

Pharmacologic inhibition of GSK-3 suppressed growth of human pancreatic tumor explants in mice, consistent with the loss of expression of oncogenic genes such as c-myc and TERT.

“GSK-3 promotes activity of a protein called NF-kappaB. Our lab has been studying NF-kappaB for a number of years and has published that this protein is important in KRAS signaling. But how KRAS activates NF-kappaB has not been well understood. We have found a link, ” said senior author Dr. Albert Baldwin, professor of biology at the University of North Carolina. “Our data suggest that GSK-3 alpha is really an onco-protein and that KRAS utilizes GSK-3 alpha to activate both NF-kappaB 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.”

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