University of Michigan researchers announced on April 6 that they have identified a new therapeutic target that may help overcome treatment resistance in gastroenteropancreatic neuroendocrine tumors, or GEP-NETs. These tumors arise from neuroendocrine cells, which are found throughout the body and act as both nerve and hormone-producing cells.
The discovery is significant because current treatments for GEP-NETs often lose effectiveness over time. Patients typically receive drugs targeting mTOR, a protein involved in cell growth, but these medications only slow tumor progression temporarily before resistance develops.
In their study, the research team screened for pathways that could be targeted in GEP-NETs and found that PIKfyve—a molecule already studied in other cancers—was present at higher levels in these tumors than in normal tissue. "PIKfyve was present in higher levels in GEP-NETs compared to the normal surrounding tissues," said Yuanyuan Qiao, Ph.D., Research Assistant Professor of Translational Pathology. "That suggested PIKfyve has a role in either promoting GEP-NET survival or growth."
Using tumor models, the scientists demonstrated that inhibiting PIKfyve reduced both tumor volume and weight compared to controls. They also discovered that PIKfyve influences autophagy—the process by which cells recycle components—and affects lipid synthesis through a pathway distinct from mTOR.
Further experiments showed that targeting both PIKfyve and mTOR together led to fewer tumors and longer survival times for mice with pancreatic neuroendocrine tumors than targeting either pathway alone. While there are currently no FDA-approved inhibitors of PIKfyve, the researchers hope ESK981—a drug now being tested at phase 2 trials—could eventually be used alongside mTOR inhibitors.
"By co-targeting these complementary mechanisms, we can transform a largely growth-suppressive therapy into one that more effectively drives tumor cell death, offering a promising new strategy to overcome treatment resistance," said Arul Chinnaiyan, M.D., Ph.D., S.P. Hicks Endowed Professor of Pathology. "The next step, of course, will be to evaluate this approach in patients with gastroenteropancreatic neuroendocrine tumors."
