Abstract
Glioblastoma (GBM) is the most common and lethal primary intrinsic tumour of the adult brain and evidence indicates disease progression is driven by glioma stem cells (GSCs). Extensive advances in the molecular characterization of GBM allowed classification into proneural, mesenchymal and classical subtypes, and have raised expectations these insights may predict response to targeted therapies. We utilized GBM neurospheres that display GSC characteristics and found activation of the PI3K/AKT pathway in sphere-forming cells. The PI3Kα selective inhibitor alpelisib blocked PI3K/AKT activation and inhibited spheroid growth, suggesting an essential role for the PI3Kα catalytic isoform. p110α expression was highest in the proneural subtype and this was associated with increased phosphorylation of AKT. Further, employing the GBM BioDP, we found co-expression of PIK3CA with the neuronal stem/progenitor marker NES was associated with poor prognosis in PN GBM patients, indicating a unique role for PI3Kα in PN GSCs. Alpelisib inhibited GSC neurosphere growth and these effects were more pronounced in GSCs of the PN subtype. The antineoplastic effects of alpelisib were substantially enhanced when combined with pharmacologic mTOR inhibition. These findings identify the alpha catalytic PI3K isoform as a unique therapeutic target in proneural GBM and suggest that pharmacological mTOR inhibition may sensitize GSCs to selective PI3Kα inhibition.
Highlights
Glioblastoma (GBM) is the most common and lethal primary intrinsic tumour of the adult brain and evidence indicates disease progression is driven by glioma stem cells (GSCs)
Increasing evidence indicates that key aspects of cancer stem cells (CSCs) function are dependent on phosphatidylinositol-3 kinase (PI3K) signalling[21], while activation of the PI3K/AKT/mammalian target of rapamycin pathway is associated with poor prognosis in GBM p atients[22]
As alternative mTOR pathways may sustain cancer cell survival in the presence of alpelisib and PI3Kα inhibition[34,35,36], we examined whether concurrent mTOR inhibition potentiates alpelisib mediated inhibitory effects
Summary
Glioblastoma (GBM) is the most common and lethal primary intrinsic tumour of the adult brain and evidence indicates disease progression is driven by glioma stem cells (GSCs). Numerous studies provided strong evidence for glioma stem cells (GSCs) being associated with intratumoural cellular heterogeneity[4,5,12,13,14,15,16] and plasticity[17,18,19,20], both major factors contributing to the poor prognosis and recurrence of GBM patients These characteristics have fuelled the concept that therapeutic approaches must include strategies tailored to target the GSC population to block GBM growth and prevent recurrence. In GSCs the regulatory PI3K subunit p85 directly interacts with CD133, a marker for both neural stem cells and brain CSCs, and this CD133 association promotes activation of the PI3K/ AKT pathway, providing further evidence for a distinct and crucial role for PI3K in G SCs28. Given that CD133 expressing cells contribute to glioma radioresistance[17], inhibition of PI3Kα might be an effective approach for specific targeting of therapy resistant GSCs
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