Role of Dopamine Receptors in the Anticancer Activity of ONC201

Abstract

ONC201/TIC10 is a first-in-class small molecule inducer of TRAIL that causes early activation of the integrated stress response. Its promising safety profile and broad-spectrum efficacy in vitro have been confirmed in Phase I/II trials in several advanced malignancies. Binding and reporter assays have shown that ONC201 is a selective antagonist of the dopamine D2-like receptors, specifically, DRD2 and DRD3. We hypothesized that ONC201’s interaction with DRD2 plays a role in ONC201’s anticancer effects. Using cBioportal and quantitative reverse-transcription polymerase chain reaction analyses, we confirmed that DRD2 is expressed in different cancer cell types in a cell type–specific manner. On the other hand, DRD3 was generally not detectable. Overexpressing DRD2 in cells with low DRD2 levels increased ONC201-induced PARP cleavage, which was preceded and correlated with an increase in ONC201-induced CHOP mRNA expression. On the other hand, knocking out DRD2 using CRISPR/Cas9 in three cancer cell lines was not sufficient to abrogate ONC201’s anticancer effects. Although ONC201’s anticancer activity was not dependent on DRD2 expression in the cancer cell types tested, we assessed the cytotoxic potential of DRD2 blockade. Transient DRD2 knockdown in HCT116 cells activated the integrated stress response and reduced cell number. Pharmacological antagonism of DRD2 significantly reduced cell viability. Thus, we demonstrate in this study that disrupting dopamine receptor expression and activity can have cytotoxic effects that may at least be in part due to the activation of the integrated stress response. On the other hand, ONC201’s anticancer activity goes beyond its ability to antagonize DRD2, potentially due to ONC201’s ability to activate other pathways that are independent of DRD2. Nevertheless, blocking the dopamine D1-like receptor DRD5 via siRNA or the use of a pharmacological antagonist promoted ONC201-induced anticancer activity.

Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G1 arrest independent of DRD2

“…8E). This is supported by work from Kline et al (46), which showed that a novel DRD2 antagonist, ONC201, can lead to reduced cell proliferation in both control and DRD2 knockout colorectal cancer cells. The mechanisms by which these DRD2-independent effects occur are unknown, but they may offer insight into interesting new drug targets for TNBC.…”

Dopamine Receptor D5 is a Modulator of Tumor Response to Dopamine Receptor D2 Antagonism

“…Induction of serum prolactin, a surrogate biomarker of DRD2 antagonism, was detected in ONC201-treated patients (10,11). Additionally, disrupting DRD2 expression in tumor cells modulated ONC201-mediated apoptosis and induction of integrated stress response (31).…”

Illuminating the Onco-GPCRome: Novel G protein–coupled receptor-driven oncocrine networks and targets for cancer immunotherapy

“…S1G), whereas M1 muscarinic receptors (CHRM1) and ␤1-adrenergic receptors (ADRB1) are highly expressed in prostate cancer, the latter receptor being of unexpected importance for the most highly prevalent cancer among males (see below). Another interesting finding was the high level of expression of dopamine receptor 2 (DRD2) in a well-defined set of cancers, including GBM, considering that a new family of antagonists for this receptor has exhibited encouraging anti-tumor activity in multiple cancer types (125,126).…”