Summary:
- Researchers disrupted a fat-recycling process to suppress pancreatic tumor growth.
- Dual targeting of lipid metabolism and KRAS signaling significantly reduced cancer in preclinical models.
- Findings point to a promising new therapeutic avenue for one of the deadliest cancers.
Pancreatic cancer, among the most lethal forms of cancer, is notoriously difficult to detect and treat. It often goes unnoticed until it has reached an advanced stage, contributing to a grim 5-year survival rate of just 13%. But new findings published in Nature on April 23, 2025, suggest that disrupting how pancreatic cancer cells process fat could be a game-changer in treatment strategies.
A research team from the University of Michigan, led by Drs. Yuanyuan Qiao, Costas Lyssiotis, and Arul Chinnaiyan, investigated the PIKfyve enzyme, a key player in lysosome function — the cell’s recycling center. Their study focused on pancreatic ductal adenocarcinoma, the most common form of the disease.
Key Findings:
- PIKfyve as a Target:
Genetically modified mice lacking PIKfyve were significantly less prone to pancreatic tumor formation. This enzyme appears non-essential for normal pancreatic function, but critical for tumor development. - Inhibiting PIKfyve Works:
Two PIKfyve inhibitors, ESK981 and apilmod, previously tested in early-stage clinical trials for other cancers, successfully slowed tumor growth in mice with pancreatic cancer. - Fat Metabolism Connection:
Further analysis revealed that PIKfyve inhibition interferes with lipid metabolism—the way cells process fats. Tumor cells attempted to compensate by activating the KRAS–MAPK pathway, a known regulator of cell metabolism and growth. - Dual Attack Strategy:
When researchers blocked both PIKfyve and the KRAS–MAPK pathway, the results were dramatic: tumor cells were either greatly reduced or eliminated in both mouse and human models.
“The most exciting aspect of our findings is the discovery of a novel strategy to rewire lipid metabolism and significantly enhance the efficacy of KRAS inhibitors—therapies already approved for pancreatic cancer treatment,”
— Dr. Arul Chinnaiyan, University of Michigan
These results open a potential new treatment pathway: reprogramming how cancer cells use fat to survive. While further clinical studies are needed, especially in human patients, the combination of PIKfyve inhibitors and KRAS-targeted drugs could represent a breakthrough approach in combating pancreatic cancer.
Source:
National Institutes of Health (NIH), Nature, April 23, 2025
🔗 NIH Research Highlights
Note: Both PIKfyve inhibitors mentioned have passed Phase 1 trials, improving the feasibility of rapid translation into clinical settings for pancreatic cancer, pending further trials.
