Abstract A107: Diacylglycerol kinase B mediates radioresistance by regulating mitochondrial lipotoxicity in glioblastoma

Abstract

Abstract Glioblastoma (GBM) is a malignant primary brain tumor in which the standard treatment, ionizing radiation (IR), achieves a median survival of about 15 months. GBM cells that survive radiotherapy contribute to tumor progression and recurrence with metabolic rewiring. We established radioresistant GBM cells and identified that diacylglycerol kinase B (DGKB), a regulator of the intracellular concentration of diacylglycerol (DAG), is significantly downregulated in these cells. The downregulation of DGKB increases DAG accumulation and reduces fatty acid oxidation, conferring radioresistance by reducing mitochondrial ROS. Diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the formation of triglycerides from DAG, is also increased in radioresistant GBM cells. Genetic inhibition of DGAT1 using miR-3918 mimic suppresses radioresistance. We discover that cladribine, an FDA-approved drug, activates DGKB and inhibits DGAT1 and sensitizes GBM cells to radiotherapy. Taken together, our study demonstrates that DGKB downregulation and DGAT1 upregulation contribute to radioresistance by reducing mitochondrial ROS and suggests DGKB and DGAT1 as therapeutic targets to overcome GBM radioresistance. [This research was supported by National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2020M2D9A2094156) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00207904).] Citation Format: Haksoo Lee, Hyunkoo Kang, Eunguk Shin, BuHyun Youn. Diacylglycerol kinase B mediates radioresistance by regulating mitochondrial lipotoxicity in glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A107.