Abstract A011: NRBF2 induces radioresistance by increasing autophagy mediated metabolite replenishment in glioblastoma

Abstract

Abstract Glioblastoma (GBM) is the most lethal brain tumor. Despite the standard of care using radiotherapy and temozolomide, the 5-year recurrence rate of GBM after the treatments is nearly 90% and, notably, about 80% of GBM recurrences occur within radiation treatment fields. Cancer cells possess dynamical metabolic reprogramming to evade cancer therapy and promote their survival. For enhancing metabolic reprogramming and metabolic plasticity, cancer cells need diverse metabolic fuel sources. In this study determined that autophagy, a common representative cell homeostasis mechanism, was upregulated upon ionizing radiation (IR) treatment on GBM cells. Nuclear receptor binding factor 2 (NRBF2), which is a positive regulator of the autophagy initiation step, was found to be upregulated in a GBM cells and GBM orthotopic xenograft mouse model. Furthermore, ATP production and the oxygen consumption rate (OCR) increased upon activation of NRBF2-mediated autophagy. It was also discovered that changes in metabolic state were induced by alterations in metabolite levels caused by autophagy, thereby causing radioresistance. To inhibit NRBF2 mediated GBM radioresistance, we found that druggable inhibition with lidoflazine, thereby suppressing IR-induced migration, invasion, proliferation, autophagic flux and improving the survival of orthotopic GBM-bearing mice. In summary, we propose that the upregulation of NRBF2 levels reprograms the metabolic state of GBM cells by activating autophagy, thus establishing NRBF2 as a potential therapeutic target for regulating radioresistance of GBM during radiotherapy. [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: Eunguk Shin, Hyunkoo Kang, Haksoo Lee, BuHyun Youn. NRBF2 induces radioresistance by increasing autophagy mediated metabolite replenishment 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 A011.