Abstract A036: Nanoparticle targeting in platinum-resistant ovarian cancer reveals dual axis of therapeutic vulnerability involving cholesterol uptake and cell redox balance

Abstract Platinum (Pt) is the main therapy for ovarian cancer (OC) ; however, most patients develop Pt resistance (Pt-R). We show that Pt-R OC cells increase intracellular cholesterol through uptake via the HDL receptor, scavenger receptor type B-1 (SR-B1). SR-B1 blockade using synthetic cholesterol-poor HDL-like nanoparticles (HDL NPs) diminished cholesterol uptake leading to cell death and suppressed tumor growth. Reduced cholesterol accumulation induced lipid oxidative stress through reduction of glutathione peroxidase 4 (GPx4) leading to ferroptosis. In turn, GPx4 depletion is associated with reduced cholesterol uptake and re-sensitized OC cells to Pt. Mechanistically, GPx4 knockdown induced decreased expression of EP300, leading to reduced H3K27Ac on the SREBP2 promoter. Suppressed SREBP2 caused the downregulation of SR-B1. Thus, chemoresistance and cancer cell survival under a high ROS burden obligate high GPx4 and SR-B1 expression through SREBP2. Targeting SR-B1 to modulate cholesterol uptake inhibits this axis and causes ferroptosis in vitro and in vivo in Pt-R OC. Citation Format: Yinu Wang, Andrea Calvert, Cardenas Horacio, Fukai Chen, Russell Keathley, Ji-Xin Chen, Shad Thaxton, Daniela Matei. Nanoparticle targeting in platinum-resistant ovarian cancer reveals dual axis of therapeutic vulnerability involving cholesterol uptake and cell redox balance abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr A036.