'Achilles heel' of pancreatic cancer identified

A research team at Georgetown Lombardi Comprehensive Cancer Center reports that inhibiting a single protein completely shuts down growth of pancreatic cancer, a highly lethal disease with no effective therapy.

Their study, to be published May 6th in Science Signaling, demonstrates in animal models and in human cancer cells that while suppressing Yes-associated protein (Yes) did not prevent pancreatic cancer from first developing, it stopped any further growth.

"We believe this is the true Achilles heel of pancreatic cancer, because knocking out Yes crushes this really aggressive cancer. This appears to be the critical switch that promotes cancer growth and progression," says the study's senior investigator, Chunling Yi, PhD, an assistant professor of oncology at Georgetown Lombardi.

Yi added that because Yes is over-expressed in other cancers, such as lung, liver and stomach tumors, researchers are already working on small molecule drugs that will inhibit activity of the protein and its partnering molecules.

The study was conducted in mouse models of pancreatic ductal adenocarcinoma (PDAC), which accounts for all but five percent of human pancreatic cancers. These mice have a mutation in the KRAS gene, as well as a mutation in their p53 gene. "More than 95 percent of pancreatic cancer patients have a KRAS mutation and about 75 percent have a mutation in p53, so these mice provide a natural model of the human disease," she says.

Because it has been very difficult to devise drugs that target either KRAS or p53, in this study the researchers looked for other potential druggable targets involved in uncontrolled growth of pancreatic cancer.

They found that Yes was over-expressed in both mouse models and human samples of PDAC, and they discovered that the KRAS mutation found in most pancreatic cancer activates Yes. "The KRAS mutation uses Yes to make cancer cells grow, so shutting down Yes defuses the mutated gene's activity," Yi says.

Yes also shuts down activity of the p53 oncogene, though the link between p53 and Yes is not yet known.

"KRAS and p53 are two of the most mutated genes in human cancers, so our hope is that a drug that inhibits Yes will work in pancreatic cancer patients - who have both mutations - and in other cancers with one or both mutations," Yi says.

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Georgetown Lombardi co-authors include oncologist and professor Anton Wellstein, MD, PhD, and pediatric oncologist and professor Jeffrey Toretsky, MD.

The authors report having no personal financial interests related to the study.

External funding for this research provided by the National Cancer Institute (CA71508), a Burroughs Wellcome Clinical Scientist Award in Translational Research and the National Institutes of Health (R01CA133662 and R01CA138212).