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Apr 04, 2013
 |  BC Innovations  |  Targets & Mechanisms

Glutamine metabolism drives PDAC

Researchers at the Dana-Farber Cancer Institute have identified a glutamine metabolism pathway that is activated by oncogenic K-Ras in pancreatic cancers.1 Moreover, the team found three different enzyme targets within the pathway that could be blocked to specifically inhibit proliferation of the malignant cells.

Cancer cells have higher metabolic demands than normal cells due to their high levels of growth and proliferation. This increased rate of glycolysis, dubbed the Warburg effect, helps sustain tumor growth.

Recent studies have shown that some oncoproteins, including c-Myc (MYC) and K-Ras, which are known to activate genes involved in cancer cell proliferation, also act as drivers for cancer metabolism.

In a 2012 paper published in Cell, a Dana-Farber team led by Alec Kimmelman identified two K-Ras-activated glucose metabolism pathways in pancreatic cancer cells. Inhibiting the pathways helped stop cancer cell proliferation.2

The K-Ras oncogene is expressed in various cancer types, including about 90% of pancreatic cancers. It is associated with poor prognosis and causes resistance to cancer drugs including epidermal growth factor receptor (EGFR) inhibitors. Attempts to target the oncogene directly have not been successful due to the complex biology and interactions of the enzyme's mutant form.

Building on their previous work, Kimmelman and colleagues found that K-Ras activated an anabolic glutamine metabolic pathway specifically in the cancer cells that not only generated energy and building blocks for protein synthesis but also regulated redox homeostasis to allow cancer cell growth.

Kimmelman is an assistant professor of radiation oncology at Harvard Medical School and Dana-Farber. The paper also included researchers from the Beth Israel Deaconess Medical Center, The University of Texas MD Anderson Cancer Center, Weill Cornell Medical College and Massachusetts General Hospital.

Healthy cells employ a glutamine metabolic pathway that converts glutamine-derived glutamate to a-ketoglutarate (a-KG) using the enzyme glutamate dehydrogenase 1 (GLUD1). a-KG is then used to fuel the tricarboxylic acid (TCA) cycle to create energy. In healthy cells, glutamine also...

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