A genetic vulnerability in clear cell renal cell carcinoma, the most aggressive type of kidney cancer, may lend itself to a combination treatment strategy that causes the cancer cells to self-destruct, according to recent research published in the .
The drug belzutifan, sold under the name Welireg, is partially effective in treating this cancer, according to , the John M. and Mary Jo Boler Collegiate Professor and associate chair in the Department of Biological Sciences at the University of Notre Dame. Unfortunately, some tumors are inherently resistant to the drug while others can develop resistance. Lu and collaborators determined that combining it with a laboratory-made protein called recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) significantly increased the death of tumor cells in laboratory tests and in聽models.
Most people who develop clear cell renal cell carcinoma have von Hippel-Lindau (VHL) syndrome, which is caused by a mutation in a tumor suppressor gene VHL, though other people can develop the cancer as well.
Lu and collaborators discovered that losing the VHL gene ignites another protein, HIF-2-alpha, causing it to create high levels of natural TRAIL inside the cell. TRAIL normally triggers cell death, called apoptosis, when it locks onto receptors on the cancer cells. However, the high level of TRAIL traps its own 鈥渄eath鈥� receptors deep inside the cell, preventing any external treatments from reaching them. It also speeds up the cell cycle, causing tumors to increase in size.
Using a recombinant form of TRAIL鈥攅ssentially a lab-produced version of the protein鈥攁nd combining it with the belzutifan was key: The belzutifan reduced the HIF-2-alpha protein. This also reduces the amount of natural TRAIL inside the cell, freeing up the hidden death receptors and sending them back to the surface, said Lu, who is affiliated with the聽 as well as the , and the .
After reducing the amount of the natural TRAIL protein, Lu and collaborators then introduce the recombinant TRAIL to latch onto the newly exposed receptors.
鈥淭his is really kind of magical, because when you reduce TRAIL, you can reduce cell division, cell proliferation, and make the cell more vulnerable to apoptosis,鈥� he said. 鈥淵ou really kind of force the cells into this corner where they can鈥檛 divide well.鈥�
Because belzutifan is already FDA-approved and TRAIL-activating therapies are undergoing clinical trials, this combination therapy is a hopeful step in treating clear cell renal cell carcinoma, Lu said.
When he presented the research at a major urology conference, "the physicians, they're excited about this," he said. "They all know this belzutifan resistance is something they have to overcome."
In addition to researchers at Notre Dame, other collaborators included researchers from the University of Galway in Ireland. Support for the project came from the Boler Family Foundation, the Naughton Faculty Research Accelerator Program, and the .
Contact: Brandi Wampler, associate director of story development, 574-631-2632,聽brandiwampler@nd.edu
Originally published by at on September 09, 2026.