Role of Hexokinase 2 (HK2) in Modulating Tumor Metabolism and Response to Therapy in Glioblastoma

Glioblastoma (GBM), similar to many other cancers, exhibits enhanced aerobic glycolysis with concomitant lactate production, a phenomenon known as the Warburg effect. We have demonstrated that preferential expression of Hexokinase 2 (HK2) is a critical mediator of metabolic reprograming in GBMs and its inhibition is a potential therapeutic strategy for sensitization of GBM tumors to radiation (RAD) and/or temozolomide (TMZ). Our results indicate that conditional HK2 inhibition disrupts energy homeostasis and sensitizes GBMs to radiochemotherapy under hypoxia. In GBM xenografts, conditional HK2 loss sensitizes GBM tumors to concomitant RAD/TMZ and results in a significant survival benefit in the mice. Moreover, loss of HK2 resulted in GBM remodeling with HK2 knockdowns showing increased necrosis, hypoxia, inflammatory infiltration and reduced vascularization. We anticipate that targeting a key metabolic enzyme involved in the Warburg effect might improve the efficacy of current therapeutic regimen and provide a unique paradigm for the management of GBMs.MAS