Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment
Ayenachew Bezawork-Geleta1, Diane Moujalled2,3, David P De Souza4
1Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia.
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.
Insights
The dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 selectively kills EGFRWT glioblastoma by altering cell metabolism. This drug impacts lipid synthesis and oxidation, offering precision medicine insights for glioblastoma treatment.
Area of Science:
- Oncology
- Cancer Metabolism
- Neuro-oncology
Background:
- Glioblastoma (IDH-wildtype) presents significant treatment challenges.
- Cancer cell metabolic reprogramming is crucial for tumor growth and drug resistance.
- The metabolic role in glioblastoma during therapy is not well understood.
Purpose of the Study:
- To investigate the metabolic effects of the DHODH inhibitor BAY2402234 on glioblastoma cells.
- To determine the efficacy of BAY2402234 in EGFRWT and EGFRvIII patient-derived glioblastoma cell lines.
Main Methods:
- Utilized patient-derived glioblastoma cell lines (EGFRWT and EGFRvIII).
- Administered the DHODH inhibitor BAY2402234.
- Analyzed metabolic phenotypes, including lipid synthesis, fatty acid oxidation, and signaling lipid species.
Main Results:
- BAY2402234 demonstrated selective cytotoxicity against EGFRWT glioblastoma cells.
- At sublethal doses, BAY2402234 induced triglyceride synthesis and reduced membrane lipid synthesis and fatty acid oxidation in EGFRWT cells.
- EGFRvIII glioblastoma cells showed minimal response to BAY2402234.
- BAY2402234 decreased signaling lipid species in EGFRWT glioblastoma.
Conclusions:
- BAY2402234 exhibits mutation-specific efficacy in glioblastoma.
- The drug alters metabolic plasticity, specifically lipid metabolism, in EGFRWT glioblastoma.
- Findings provide insights for precision medicine strategies targeting glioblastoma metabolism.
