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Mutated Kras spins a molecular loop that launches pancreatic cancer
Date:1/26/2012

HOUSTON Scientists have connected two signature characteristics of pancreatic cancer, identifying a self-perpetuating "vicious cycle" of molecular activity and a new potential target for drugs to treat one of the most lehal forms of cancer.

The research, reported in the journal Cancer Cell and led by scientists at The University of Texas MD Anderson Cancer Center, connected the molecular dots between:

  • Mutated versions of Kras, a gene that acts as a molecular on-off switch but gets stuck in the "on" position when mutated.
  • Heightened activity of a protein complex called NF-B that controls activation of genes.

"Kras is mutated in 80 to 95 percent of pancreatic ductal adenocarcinomas, and is the most frequent mutation among all cancers," said senior author Paul Chiao, Ph.D., professor in MD Anderson's Department of Molecular and Cellular Oncology.

About 42,000 new cases of pancreatic ductal adenocarcinoma are diagnosed in the United States each year. Estimates vary, but the 5-year survival rate has been 1 to 3 percent for decades and median survival after diagnosis is six months, the researchers note.

Interleukin-1α is a new potential drug target

"There have been many attempts to inhibit mutated Kras, but it's an elusive target that so far has defied treatment," Chiao said. "So if we can't hit Kras, maybe we can target one of its downstream genes. This research identifies some of those genes and suggests that interleukin-1apha (IL-1α) is a potential therapeutic target."

Chiao and colleagues identified IL-1α as a crucial player in a feed-forward loop that:

  • Begins with mutationally activated Kras triggering a chain reaction that induces IL-1α expression;
  • This in turn activates NF-κB via the protein kinase IKK2/β, which blocks the inhibitor of NF-κB.
  • In the cell nucleus, NF-κB oversees gene transcriptio
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

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