Pancreatic Cancer Cells Vulnerable to Glutamine Pathway Inhibitors

While most cells use glutamate dehydrogenase (GLUD1) to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle (Kreb's cycle), PDAC was shown to rely on a distinct pathway in which glutamine-derived aspartate was transported into the cytoplasm where it was converted into oxaloacetate by aspartate transaminase (GOT1). Subsequently, this oxaloacetate was converted into malate and then pyruvate, increasing the NADPH/NADP+ ratio, which could then maintain the cellular redox state.

PDAC cells were strongly dependent on this series of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway led to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions resulted in a pronounced suppression of PDAC growth in vitro and in vivo.

Reprogramming of glutamine metabolism by PDAC was found to be mediated by the KRAS oncogene. The protein product of the normal KRAS (Kirsten rat sarcoma viral oncogene) 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.

“Pancreatic cancer cells have painted themselves into a metabolic bottleneck,” said senior author Dr. Alec Kimmelman, assistant professor of radiation oncology at the Dana-Farber Cancer Institute. “If you suppress any enzyme in that pathway, the cancer cells cannot effectively compensate and they can no longer grow. We do not have a drug to do this in humans, but we are working on inhibitors of enzymes in the glutamine pathway.”

Related Links:
Dana-Farber Cancer Institute