DRD4 Selectively Promotes Glioblastoma Stem Cell Growth

Glioblastoma (GBM) is initiated and maintained by a subpopulation of GBM neural stem cells (GNS) that likely need to be eliminated for effective disease control. As GBMs grow in a neurochemical-rich microenvironment, Dolma and colleagues screened 680 neurochemical compounds to identify selective inhibitors of GNS growth. Ten GNS-selective inhibitors were discovered that were enriched for modulators of dopaminergic, serotonergic, and cholinergic pathways, suggesting these as putative targets for GBM. Two of the compounds were antagonists of dopamine receptor D4 (DRD4) and selectively suppressed the growth of GNS cells and reduced the clonogenic potential of GBM cells. GBM samples expressed DRD4, and expression data from The Cancer Genome Atlas (TCGA) revealed that patients with GBM with high DRD4 expression had worse survival than those with low expression, suggesting that DRD4 expression is clinically relevant. Gene expression analysis revealed DRD4 antagonism in GNS cells repressed expression of DNA replication and cell-cycle progression genes, and enhanced expression of genes involved in lipid metabolism and autophagy. Consistent with these findings, DRD4 antagonism induced G₀/G₁ cell-cycle arrest and apoptosis and resulted in the accumulation of autophagic vacuoles and cholesterol. The accumulation of autophagosomes and disruption of autophagic flux was due to inhibition of lysosomal function, and promoted cytotoxicity in response to DRD4 antagonism. DRD4 antagonists exhibited synergism in vitro with temozolomide (TMZ), the current standard of care for GBM, raising the possibility that DRD4 antagonists may improve the efficacy of TMZ treatment in patients with GBM, and in subcutaneous and intracranial GBM xenograft models, DRD4 antagonists reduced tumor growth and increased survival. These results implicate neurochemical signaling activity in GBM pathogenesis and support further exploration of DRD4 antagonists or inhibitors of autophagic flux for the treatment of GBM.

Dolma S, Selvadurai HJ, Lan X, Lee L, Kushida M, Voisin V, et al. Inhibition of dopamine receptor D4 impedes autophagic flux, proliferation, and survival of glioblastoma stem cells. Cancer Cell 2016;29:859–73.