Abstract
INTRODUCTION
Imipridones selectively target G protein-coupled receptors (GPCRs) that control critical signaling pathways in various cancer cells. Aberrant overexpression of GPCRs has been implicated in tumorigenesis. ONC201, a first generation imipridone that directly antagonizes dopamine receptor D2 (DRD2), continues to be evaluated in clinical trials for advanced cancers. The immediate downstream mechanism(s) of DRD2 inhibition and resulting anti-cancer activity remains an area of active study. METHODS &
RESULTS
ONC206, an analog of ONC201, shares the same imipridone core chemical structure and selective antagonism of DRD2, potently inhibits treatment-resistant glioblastoma caused by intra-tumoral heterogeneity with clinically achievable concentrations. In silico analysis of a glioma patient database revealed that alteration of DRD2 mRNA expression was directly connected to global gene expression change. Imaging DRD2 expression by immunofluorescence demonstrated heterogeneous expression of DRD2 in the glioblastoma cells. After DRD2 inhibition, global metabolite profiling in patient-derived glioblastoma stem cells (GSCs) compared with differentiated glioblastoma cells (DGCs) demonstrated globally differential effects in their cellular signaling pathways. Cell viability assay showed that exposure to ONC206 in a dose dependent manner preferentially eliminated GSCs with 50 to 200 nM of IC50 ranges, whereas the IC50 of DGCs ranged from 200 to 1000 nM. In vitro limiting dilution and sphere formation assay showed that ONC206 prevented tumor sphere formation and tumor growth. ONC206 down-regulated protein expression of cancer-related stem cell markers in the GSCs; silencing DRD2 expression confirmed the dependency of DRD2 expression on cancer stem cell niches in glioblastoma.
CONCLUSIONS
ONC206 treatment displays the differential effects on glioblastoma cells, more selectively targeting DRD2 in GSCs (at nanomolar concentrations) compared with DGCs in culture and in xenograft models. This suggests that a therapeutic strategy targeting DRD2-expressing GSCs within glioblastoma may be beneficial for overcoming the therapeutic resistance.