– The build-up of fumarate due to the loss of fumarate hydratase (FH) can lead to cellular changes and cause a severe form of kidney cancer called hereditary leiomyomatosis and renal cell cancer (HLRCC).
– Researchers examined 74 FH variants with uncertain cancer-related risks and found that more than half were enzymatically inactive, indicating a strong likelihood of causing cancer.
– The researchers discovered that excess fumarate hinders the creation of purines, a type of organic compound, making FH-deficient cells depend on a secondary process called purine salvage for growth.
– By genetically or pharmaceutically blocking this secondary purine salvage process, the growth of HLRCC tumors was reduced, suggesting potential treatment strategies for FH-deficient tumors.

Reference:

1.) Blake R. Wilde, Nishma Chakraborty, Nedas Matulionis, Stephanie Hernandez, Daiki Ueno, Michayla E. Gee, Edward D. Esplin, Karen Ouyang, Keith Nykamp, Brian Shuch, Heather R. Christofk; FH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer. Cancer Discov 2023; https://doi.org/10.1158/2159-8290.CD-22-0874