University of North Carolina Lineberger Comprehensive Cancer Center researchers and colleagues have discovered an important and significant overlap in genes regulated by the activity of three proteins, RAS, MYC and TEAD, that support the growth of pancreatic cancer. They also found that combining RAS-targeted drugs with anti-TEAD drugs was more effective at inhibiting pancreatic cancer growth than either drug alone.
The laboratory research findings were presented as a late-breaking abstract on April 29, 2025, at the American Association of Cancer Research (AACR) annual meeting in Chicago.
After decades of research, drugs have been developed that target the predominant driver of pancreatic cancer, a protein known as KRAS. Despite this achievement, resistance to these drugs remains a major challenge. The goal of this study was to determine which genes are implicated in the resistance to KRAS-targeted drugs and how that resistance could be overcome.
“KRAS-driven cancers are far more targetable than they were a dozen years ago. Indeed, the FDA approval of KRAS G12C inhibitors in the early 2020s marked a major milestone in cancer drug discovery, and now there are more than 45 drugs in over 160 clinical trials targeting not just KRAS G12C, but several RAS proteins,” said Brandon Mouery, PhD, first author of the abstract and a postdoctoral fellow in the lab of Channing Der, PhD, at UNC Lineberger. “However, not all cancers respond to RAS inhibitors, and among those that do, resistance can develop within months. It is now clear that RAS inhibitors alone will not be sufficient, so we need to find effective drug combinations to overcome resistance and enhance the efficacy of RAS inhibitors.”
The investigators first wanted to know which genes and their protein products were implicated in resistance to pancreatic cancer drugs such as RAS inhibitors. Looking at both mouse and human pancreatic cancer cells in the laboratory, the researchers found a high degree of overlap between genes regulated by the MYC protein and those regulated by two interdependent proteins, YAP and TEAD.
They found 3,010 MYC-dependent genes in their human pancreatic cancer cell samples, 36% of which support mutant KRAS signaling. They also found more than 3,000 TEAD-dependent genes in both mouse and human pancreatic cancer cells that had a large degree of overlap with the MYC genes they identified. The findings may prove to be significant because there are currently no drugs that directly target MYC, but knowing TEAD regulates some of the same genes as MYC should provide an alternative approach to suppressing MYC-dependent gene expression.
The researchers also treated the cancer cells with different drugs and found that the combination of drugs that inhibited both TEAD and RAS led to a more robust tamping down of essential gene expression than either single treatment, thereby supporting the concept of combining TEAD and RAS inhibitors. However, it is unclear how effective and well-tolerated TEAD inhibitors will be in people, but it is known that RAS inhibitors are effective and tolerated. Testing TEAD inhibitors in humans for safety is a planned future step for the investigators.
“UNC efforts are very prominent in the field of RAS research as researchers recently published two articles that set the standard in the field for how KRAS signaling works in KRAS-mutant cancers. For patients, most significantly, UNC researchers were part of a team that reported the activity of a novel RAS inhibitor that targets all RAS proteins and is now in phase III clinical trials for the treatment of pancreatic cancer,” Mouery said. “We believe that our current research finding will add to the success of finding better ways to treat this still highly lethal cancer.”
Authors and disclosures
A complete listing of authors is available in the published abstract. Mourey and Der report no conflicts of interest.
The research was funded in part by grants from the National Cancer Institute, Pancreatic Cancer Action Network, Pancreatic Cancer Action Network-AACR Research Acceleration Network and the Department of Defense.