RESUMEN
Glioblastoma (GBM) is the deadliest adult brain cancer. Under the current standard of care, almost all patients succumb to the disease and novel treatments are urgently needed. Recognizing that GBMs are addicted to cholesterol, past clinical trials have repurposed statins against GBM but failed. The purpose of this study was to test whether treatments that upregulate the cholesterol biosynthesis pathway in GBM would generate a metabolic vulnerability that can be exploited using statins and to determine the underlying mechanisms.Effects of radiotherapy and temozolomide or dopamine receptor antagonists on the mevalonate pathway in GBM were assessed in vitro and in vivo. The impact of statins on self-renewal of glioma stem cells and median survival was studied. Branches of the mevalonate pathway were probed to identify relevant effector proteins.Cells surviving combination treatments that converge in activating the immediate early response, universally upregulated the mevalonate pathway and increased stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 was inhibited by statins, which led to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.We conclude that a combination of dopamine receptor antagonists and statins could potentially improve radiotherapy outcome and warrants further investigation. SIGNIFICANCE: Combination therapies that activate the mevalonate pathway in GBM cells after sublethal treatment enhance self-renewal and migratory capacity through Rac-1 activation, which creates a metabolic vulnerability that can be further potentially exploited using statins.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Ácido Mevalónico , Temozolomida , Proteína de Unión al GTP rac1 , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Ácido Mevalónico/metabolismo , Humanos , Animales , Proteína de Unión al GTP rac1/metabolismo , Proteína de Unión al GTP rac1/antagonistas & inhibidores , Ratones , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Temozolomida/farmacología , Temozolomida/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Transducción de Señal/efectos de los fármacos , Antagonistas de Dopamina/farmacologíaRESUMEN
Glioblastoma is the deadliest adult brain cancer. Under the current standard of care almost all patients succumb to the disease and novel treatments are urgently needed. Dopamine receptor antagonists have been shown to target cancer cell plasticity in GBM and repurposing these FDA-approved drugs in combination with radiation improves the efficacy of radiotherapy in glioma models. In cells surviving this combination treatment the mevalonate pathway is upregulated at the transcriptional and functional level. Here we report that glioblastoma treatments that converge in the immediate early response to radiation through activation of the MAPK cascade universally upregulate the mevalonate pathway and increase stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 is inhibited by statins, which leads to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.
