Researchers have decoded a chain of molecules that are critical for the growth and survival of pancreatic ductal adenocarcinoma. They say their findings, published by Murakami et al in Developmental Cell, suggest that inhibiting the YAP biologic network may effectively regress early-stage pancreatic ductal adenocarcinoma and could be paired with other drugs to halt more advanced-stage tumors.

“To effectively control tumor growth, you have to know the molecular network that drives that growth."

— Chunling Yi, PhD

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Methods and Findings

Their study builds upon research that previously identified YAP as an oncogene central to the initiation of pancreatic ductal adenocarcinoma as well as a variety of other cancers. In the current study, which employed advanced animal models, researchers managed to switch off YAP in preestablished pancreatic ductal adenocarcinomas and discovered that suppressing YAP blocks the metabolic pathways that provide the fuel and building materials for maintaining the growth of the cancer.

This study revealed the “flow chart” of key molecules in the YAP signaling network, which could be used to design novel and more effective therapies for advanced pancreatic cancer, said the study’s senior investigator Chunling Yi, PhD, Associate Professor of Oncology at Georgetown Lombardi Comprehensive Cancer Center.

“Our research suggests that inhibiting YAP as well as SOX2, a molecule that gets turned on when YAP is inhibited, could be very important to long-term control of pancreatic cancer,” said Dr. Yi. “In later stages of this cancer, when a YAP inhibitor is used, SOX2 could takes its place to allow pancreatic ductal adenocarcinoma to survive and grow, so therapy that targets both molecules would be ideal.”

KRAS

Many pancreatic ductal adenocarcinomas are caused by a mutation in the oncogene KRAS. There is no approved treatment for tumors with KRAS mutations, which are found in a number of cancers. KRAS mutations activate the YAP pathway. In this study, researchers showed in animal models that the YAP protein is required for the maintenance of KRAS-mutant pancreatic ductal adenocarcinomas.

In preclinical work, researchers demonstrated that inhibiting YAP can force pancreatic ductal adenocarcinomas to regress into cells that resemble what are normally found within the organ. Eventually, however, SOX2 is activated to compensate for loss of YAP, causing some tumors to relapse.

“To effectively control tumor growth, you have to know the molecular network that drives that growth. This study takes a good look under the hood and gives us the key drivers that could be targeted to shut that engine down,” concluded Dr. Yi.

Disclosure: For full disclosures of the study authors, visit cell.com.