New Therapeutic Target in Pancreatic Cancer

The development of pancreatic cancer is driven by co-existing mutations in two genes: the oncogene KRAS, which is involved in controlling cell growth, and the tumor suppressor gene p53. But how these mutations cooperate to promote cancer has been unknown. A new study uncovers a direct link between these mutations and the mechanism that regulates cell activity, providing insight for future development of therapeutics that could hit this newly found target in pancreatic cancer.

“The most commonly mutated tumor suppressor gene in cancer, p53, dramatically rewires RNA splicing, the fundamental cell mechanism by which RNA is processed before being translated into protein,” says senior author Steven D. Leach of Dartmouth. “The rewiring is done in a manner that leads to further activation of the KRAS oncogene, the major ‘driver’ gene in human pancreatic cancer.”

The team analyzed every known mRNA splice variant encoded by the human genome—more than 200,000 possible sequences—in hundreds of pancreatic cancer patients. Their findings were published today in Cancer Cell. “Our paper shows that a new class of drugs that alter RNA splicing have selective activity against p53-mutant pancreatic cancers,” Leach says.

This study shows that there are still fundamental mechanisms to be discovered in cancer that can lead to new treatment strategies. Based on these findings, the next steps will be to design clinical trials that will evaluate these new drugs in patients with pancreatic cancer.