Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment

Bezawork-Geleta, A; Moujalled, D; De Souza, DP; Narayana, VK; Dimou, J; Luwor, R; Watt, MJ

Author(s): Bezawork-Geleta, A; Moujalled, D; De Souza, DP; Narayana, VK; Dimou, J; Luwor, R; Watt, MJ;
Details: Publication Year 2024-07-27,Volume 14,Issue #8,Page 413
Journal Title: Metabolites
Abstract: Glioblastoma (IDH-wildtype) represents a formidable challenge in oncology, lacking effective chemotherapeutic or biological interventions. The metabolic reprogramming of cancer cells is a hallmark of tumor progression and drug resistance, yet the role of metabolic reprogramming in glioblastoma during drug treatment remains poorly understood. The dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 is a blood-brain barrier penetrant drug showing efficiency in in vivo models of many brain cancers. In this study, we investigated the effect of BAY2402234 in regulating the metabolic phenotype of EGFRWT and EGFRvIII patient-derived glioblastoma cell lines. Our findings reveal the selective cytotoxicity of BAY2402234 toward EGFRWT glioblastoma subtypes with minimal effect on EGFRvIII patient cells. At sublethal doses, BAY2402234 induces triglyceride synthesis at the expense of membrane lipid synthesis and fatty acid oxidation in EGFRWT glioblastoma cells, while these effects are not observed in EGFRvIII glioblastoma cells. Furthermore, BAY2402234 reduced the abundance of signaling lipid species in EGFRWT glioblastoma. This study elucidates genetic mutation-specific metabolic plasticity and efficacy in glioblastoma cells in response to drug treatment, offering insights into therapeutic avenues for precision medicine approaches.
Publisher: MDPI
Keywords: brain cancer; lipid droplets; lipid metabolism
Research Division(s): Blood Cells And Blood Cancer
PubMed ID: 39195509
Publisher's Version: https://doi.org/10.3390/metabo14080413
Open Access at Publisher's Site: https://doi.org/10.3390/metabo14080413
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-09-02 10:42:04

Last Modified: 2024-09-02 10:54:59