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. Author manuscript; available in PMC: 2018 Aug 30.
Published in final edited form as: Transl Cancer Res. 2017 Oct;6(Suppl 7):S1239–S1243. doi: 10.21037/tcr.2017.10.03

Figure 1.

Figure 1

Mechanism of action of ONC201 in glioblastoma. Small molecule ONC201 crosses the blood brain barrier and exerts it effects against glioblastoma bulk tumor cells and cancer stem cell-like (CSC) cells. ONC201 antagonizes dopamine receptors DRD2 and DRD3. The link between dopamine receptor antagonism by ONC201 and the downstream cell death signaling pathways perturbed by ONC201 is continuing to be unraveled. ONC201 dually inhibits phosphorylation of Akt and ERK, leading to the dephosphorylation of transcription factor FOXO3A. Dephosphorylated FOXO3A translocates into the nucleus where it activates transcription of its target genes, including pro-apoptotic death receptor ligand TNF-related apoptosis inducing ligand (TRAIL). ONC201 also activates the integrated stress response (ISR) through stimulation of EIF2a kinases. Phosphorylation of EIF2α leads to induction of transcription factors ATF4 and CHOP, which then increase DR5 expression. The combined upregulation of the ligand TRAIL and its surface receptor DR5 by ONC201 ultimately triggers cancer cell death.