Abstract IA020: Exploiting cholesterol metabolism for treatment resistant ccRCC patients

Abstract

Abstract Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets (LDs) comprised primarily of free and esterified cholesterol molecules; however, the functional significance of cholesterol accumulation in ccRCC cells was unknown. We demonstrated that, surprisingly, genes encoding cholesterol biosynthetic pathway enzymes are strongly repressed in ccRCC cells, making them auxotrophic for exogenous cholesterol. Intriguingly, Mendelian randomization analyses of over 31,000 human genomes indicate a causal link between elevated serum levels of high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and ccRCC tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. We showed that Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import by ccRCC cells, and inhibiting SCARB1 expression or activity is sufficient to cause ccRCC cell cycle arrest and apoptosis accompanied by elevated intracellular reactive oxygen species (ROS) levels and decreased PI3K/AKT signaling. Collectively, our data reveal a previously unrecognized cholesterol dependency in ccRCC and implicate SCARB1 as a therapeutic target that may contribute to novel strategies for treating kidney cancer. Citation Format: M. Celeste Simon. Exploiting cholesterol metabolism for treatment resistant ccRCC patients [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 IA020.