Inhibiting a single protein completely shuts down the growth of pancreatic cancer, according to new research. Pancreatic cancer is highly lethal and has no effective therapy.
Suppressing Yes-associated protein (Yes) stopped any further growth of pancreatic cancer, though it did not stop it first developing, according to the study’s data from animal models and human cancer cells. The study was conducted at the Georgetown Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC, and published in Science Signaling (2014; doi:10.1126/scisignal.2005049).
“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,” said 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 5% 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% of pancreatic cancer patients have a KRAS mutation and about 75% have a mutation in p53, so these mice provide a natural model of the human disease,” she said.
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 said.
Yes also shuts down activity of the p53 oncogene; however, 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 said.