Abstract B008: Activation of the bile acid pathway promotes tumorigenesis in clear cell renal cell carcinoma

Abstract Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. We and others have demonstrated that elevated lipid uptake and storage is required for ccRCC cell viability; however, the role of stored cholesterol, the most abundant component in ccRCC intracellular lipid droplets, remains unclear. We recently demonstrated that ccRCC cells acquire exogenous cholesterol through the HDL receptor SCARB1, inhibition or suppression of which induces apoptosis. Here, we show that elevated expression of 3 beta-hydroxy steroid dehydrogenase type 7 (HSD3B7), which metabolizes cholesterol-derived oxysterols in the bile acid biosynthetic pathway, is essential for ccRCC cell survival. Repressing HSD3B7 expression genetically, or treating ccRCC cells with a newly identified HSD3B7 inhibitor, resulted in toxic oxysterol accumulation, impaired proliferation, and increased apoptosis in vitro and in vivo. These data demonstrate that bile acid synthesis regulates cholesterol homeostasis in ccRCC and identifies HSD3B7 as a plausible therapeutic target. Citation Format: Romain Riscal, Sarah Gardner, Madeleine Carens, Clementina Mesaros, Jimmy Xu, Nate Coffey, Leah Davis, Austin Vogt, Adam Olia, Jennifer Finan, Jason Godfrey, Ian Blair, Brian Keith, Ronen Marmorstein, Nicolas Skuli, Celeste Simon. Activation of the bile acid pathway promotes tumorigenesis in clear cell renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B008.