Pancreatic Tumours Depend on Oncogene Activity

Photo: Pancreas

The pancreas is a gland organ in
the digestive and endocrine
system; © panthermedia.net/
Peter Lamb

The findings suggest that some of these altered metabolic pathways might be potential targets for future drugs to treat the deadly cancer.

The investigators say that when they experimentally shut down the expression of the Kras oncogene in mice, the pancreatic tumours rapidly shrank, and, in some cases, left no visible signs of cancer. This outcome, they said, provides evidence that advanced pancreatic cancers are "addicted" to the Kras oncogene for their continued growth.

"This experiment allowed us to demonstrate that pancreatic cancers in their native setting are dependent on continued oncogenic Kras expression for tumour maintenance," says Doctor Alec Kimmelman.

Kimmelman said they also discovered that oncogenic Kras "basically reprograms the glucose metabolism of the cell by regulating the expression of key metabolic enzymes, some of which might provide novel therapeutic targets." If that is the case, then attacking these pathways might be more feasible than attempting to block KRAS directly, since KRAS has proven frustratingly difficult to hit with designer drugs.

It is estimated that pancreatic ductal adenocarcinoma will be diagnosed in more than 43,000 people in the United States in 2012, according to the American Cancer Society, and more than 37,300 will die from the disease, which has a 5-year survival rate of only 5 per cent.

It has been known that the Kras oncogene is an important driver of pancreatic cancer, unleashing chaotic proliferation of cancer cells, but a key question remained as to whether cancer cells that developed spontaneously in the pancreas needed Kras to survive.

To clarify this point, Kimmelman and colleagues created a genetically engineered mouse model in which the mutant Kras gene in the pancreas could be turned on and off at will through dietary manipulation. In addition, the tumour suppressor gene p53 was "knocked out" to model the loss of p53 that occurs in pancreatic cancer.

The researchers showed that the oncogene – which regulates the activity of multiple genes in cells - "reprogrammed" gene pathways that are involved in utilising and processing glucose, which serves as fuel for cells. For example, experiments revealed that Kras activity shunted glucose building blocks into a pathway called the non-oxidative pentose phosphate pathway (PPP) - a previously unknown connection. Importantly, suppressing these key metabolic enzymes regulated by Kras resulted in a significant impairment of tumour growth.

MEDICA.de; Source: Dana-Farber Cancer Institute