Advanced pancreatic tumors depend on continued oncogene activity

April 26, 2012

Researchers at Dana-Farber Cancer Institute have shown that advanced pancreatic cancers in mice can't survive without continued expression of a mutant oncogene that "rewires" key metabolic pathways to fuel the cancer cells.

The findings, published in the April 27 issue of the journal Cell, suggest that some of these altered might be potential targets for future drugs to treat the deadly .

The investigators report that when they experimentally shut down the expression of the Kras in mice, the 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 tumor maintenance," says Alec Kimmelman, MD, PhD, co-corresponding author of the report along with Ronald DePinho, MD, formerly at Dana-Farber and now at M.D. Anderson Cancer Center in Houston.

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 .

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

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 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 tumor suppressor gene p53 was "knocked out" to model the loss of p53 that occurs in pancreatic cancer.

Next, the scientists removed an antibiotic from some of the rodents' feed, which inactivated the Kras oncogene. Scans and histology showed tumors beginning to shrink within two or three days and were diminished by an average of 50 percent after a week. PET scans revealed that the remaining tumors were no longer consuming glucose, meaning they were inactive. In addition, malignant changes in the tumors' tissue environment caused by the Kras oncogene had been reversed.

In collaboration with the laboratory of Lewis Cantley, PhD, of Beth Israel Deaconess Medical Center, the investigators then determined how Kras oncogene activity enabled the tumors to survive and grow. "We found that Kras is regulating in pancreatic cancer," Kimmelman says.

The researchers showed that the oncogene – which regulates the activity of multiple genes in cells -- "reprogrammed" gene pathways that are involved in utilizing 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 regulated by Kras resulted in a significant impairment of tumor growth.

"These results suggest that it may be possible to attack tumors by inhibiting some of these enzymes," Kimmelman explains, though he cautions that it remains to be seen whether the enzymes can be reduced without having unwanted effects on the body.

Still, this research may ultimately yield new avenues for treating various cancers that are driven by the hard-to-target Kras oncogene.

Explore further: Gene linked to pancreatic cancer growth, study finds

Related Stories

Gene linked to pancreatic cancer growth, study finds

January 31, 2012
A mutant protein found in nearly all pancreatic cancers plays a role not only in the cancer's development but in its continued growth, according to a new study from University of Michigan Comprehensive Cancer Center researchers. ...

Mutant Kras drives pancreatic cancer maintenance via metabolic pathways

April 26, 2012
A genetic mutation that drives the initiation of pancreatic cancer also manipulates metabolic pathways to support tumor growth and progression, scientists report in the journal Cell.

EGFR essential for the development of pancreatic cancer

September 15, 2011
The epidermal growth factor receptor (EGFR) gene is essential for KRAS-driven pancreatic cancer development, according to study results presented at the Second AACR International Conference on Frontiers in Basic Cancer Research, ...

Potential treatment target for KRAS-mutated colon cancer found

February 16, 2012
Researchers from the Massachusetts General Hospital (MGH) Cancer Center have identified a new potential strategy for treating colon tumors driven by mutations in the KRAS gene, which usually resist both conventional and targeted ...

KRAS gene mutation and amplification status affects sensitivity to antifolate therapy

April 4, 2012
Testing patients with non-small cell lung cancer for both mutations and amplifications of the KRAS gene prior to therapy may help to predict response to treatment with antifolates, according to the updated results of a preclinical ...

Recommended for you

New study reveals breast cancer cells recycle their own ammonia waste as fuel

October 19, 2017
Breast cancer cells recycle ammonia, a waste byproduct of cell metabolism, and use it as a source of nitrogen to fuel tumor growth, report scientists from Harvard Medical School in the journal Science.

US regulators approve 2nd gene therapy for blood cancer

October 19, 2017
U.S. regulators on Wednesday approved a second gene therapy for a blood cancer, a one-time, custom-made treatment for aggressive lymphoma in adults.

New findings explain how UV rays trigger skin cancer

October 18, 2017
Melanoma, a cancer of skin pigment cells called melanocytes, will strike an estimated 87,110 people in the U.S. in 2017, according to the Centers for Disease Control and Prevention. A fraction of those melanomas come from ...

Drug yields high response rates for lung cancer patients with harsh mutation

October 18, 2017
A targeted therapy resurrected by the Moon Shots Program at The University of Texas MD Anderson Cancer Center has produced unprecedented response rates among patients with metastatic non-small cell lung cancer that carries ...

Possible new immune therapy target in lung cancer

October 18, 2017
A study from Bern University Hospital in collaboration with the University of Bern shows that so-called perivascular-like cells from lung tumors behave abnormally. They not only inadequately support vascular structures, but ...

Many pelvic tumors in women may have common origin—fallopian tubes

October 17, 2017
Most—and possibly all—ovarian cancers start, not in ovaries, but instead in the fallopian tubes attached to them.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.