TARGETING HEXOKINASE 2 IN MENINGIOMAS: UNVEILING METABOLIC VULNERABILITIES AND ADAPTIVE MECHANISMS ACROSS TUMOUR GRADES

Abstract AIMS Meningioma is the most common type of primary brain tumour, significantly impacting patients’ quality of life even after surgical intervention. While grade 1 meningiomas are classified as benign, some molecular sub- groups exhibit higher recurrence rates and resistance to conventional therapies. There is currently no effective systemic treatment for meningiomas. This study aims to investigate the role of a key glycolytic enzyme Hexok- inase 2 (HK2) in meningioma progression and assess its potential as a therapeutic target. METHODS We analysed the impact of HK2 knockdowns (KD) on meningioma cell proliferation and metabolic pathways. In vitro experiments examined the effects of HK2 KD on the gene expression of the androgen receptor (AR), Insulin Growth Factor Receptor 1 (IGF1R), glucose uptake, and lactate production. Additionally, higher-grade menin- gioma cells metabolic flexibility was evaluated under HK2 KD conditions. In vivo experiments were conducted using an NSG mouse model with HK2 KD cells to assess tumour growth, LDHA activity, and brain invasion. RESULTS HK2 KD in lower-grade meningiomas reduced androgen receptor expression, inhibiting proliferation and low- ering IGF1R levels, glucose uptake, and lactate production. In higher-grade meningiomas, HK2 KD decreased LDHA activity and proliferation, triggering metabolic shifts. Some cells transitioned from glycolysis to oxidative phosphorylation, while others showed impaired oxidative phosphorylation. These adaptations influenced sen- sitivity to the AR inhibitor enzalutamide, with resistance overcome by increasing oxidative stress using hemin, which reduced HK2 expression. In vivo, HK2 KD significantly suppressed tumour growth, LDHA activity, and brain invasion in the NSG mouse model. CONCLUSION Our findings reveal HK2’s key role in meningioma progression. In vitro and in vivo data show HK2 drives tumour growth through distinct adaptive mechanisms in different grades. Targeting HK2 offers therapeutic potential, providing insight into meningioma metabolism and highlighting HK2 and related pathways as promising targets for future treatments.