Abstract 5385: Concurrent inhibition of the serine/threonine protein kinase AURKB and the fatty acid oxidation enzyme CPT1A demonstrates synthetic lethality in preclinical glioblastoma models

Abstract Glioblastoma IDH-wild type, an aggressive and treatment-resistant brain cancer, urgently requires novel and more effective therapeutic approaches to enhance patient outcomes. Analysis of public genomic databases has revealed that the serine/threonine protein kinase Aurora kinase B may represent a promising therapeutic target for GBM. This study provided compelling evidence that AURKB is significantly upregulated in GBM tumors, and elevated AURKB levels are associated with poorer survival in GBM patients. Remarkably, the selective AURKB inhibitor barasertib was found to potently suppress the growth of established GBM cell lines, patient-derived xenograft models, and neurosphere cultures at low, nanomolar concentrations. Similarly, genetic depletion of AURKB substantially impaired the growth of patient-derived xenograft lines. Notably, in an orthotopic PDX GBM xenograft model, the loss of AURKB function was found to extend animal survival. Mechanistically, the study revealed that AURKB depletion or inhibition significantly impacts mitochondrial energy metabolism in GBM cells. Paradoxically, the loss of AURKB led to increased cellular respiration and oxidative phosphorylation, facilitated by enhanced fatty acid oxidation. Consistently, the absence of AURKB sensitized GBM cells to the cytotoxic effects of CPT1A inhibition, i.e., fatty acid oxidation inhibition. Furthermore, the BH3-mimetic ABT263 was found to reduce the growth of GBM lines in the context of AURKB loss of function, likely due to the heightened dependence on mitochondrial metabolism. These findings uncover a previously unappreciated role for AURKB in regulating GBM metabolism and provide a strong rationale for further developing AURKB-targeted therapies, potentially in combination with metabolic inhibitors and BH3-mimetics, to improve clinical outcomes for patients with GBM. Citation Format: Qiuqiang Gao, Chang Shu, Jeongyeon Mun, Zhe Zhu, Hasan O. Akman, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin. Concurrent inhibition of the serine/threonine protein kinase AURKB and the fatty acid oxidation enzyme CPT1A demonstrates synthetic lethality in preclinical glioblastoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5385.