Scientists at the University of Notre Dame have found a hidden weakness in an aggressive form of kidney cancer.

The discovery involves clear cell renal cell carcinoma. It often carries a mutation in the tumor-suppressor gene VHL.

Researcher Xin Lu and colleagues found that losing VHL overactivates a protein called HIF-2-alpha. This makes cancer cells produce large amounts of another protein, TRAIL.

TRAIL normally helps kill damaged cells by attaching to “death receptors” on their surface. But the excess TRAIL traps those death receptors inside the cell, where treatments cannot reach them.

The drug belzutifan, sold as Welireg, blocks HIF-2-alpha. The researchers showed it lowers TRAIL levels and lets the trapped death receptors move back to the surface.

Adding laboratory-made recombinant TRAIL then triggered much more cancer cell death. The combination also slowed cancer cell division.

The findings, published in the Proceedings of the National Academy of Sciences, could lead to a new combination therapy. Belzutifan alone helps some patients but many tumors resist it.

The work is still in laboratory and animal-model stages. Clinical testing will be needed before it can help patients.