Abstract 3213: Antagonism of D2-like dopamine receptors plays a role in Onc201’s anticancer effects

Abstract

Abstract ONC201/TIC10 is a first-in-class small molecule inducer of TRAIL that causes early activation of the integrated stress response and inactivates both Akt and ERK. Its promising safety profile and broad spectrum efficacy in vitro has been confirmed in Phase I/II trials in several advanced malignancies. Biochemical and reporter assays have shown that ONC201 is a selective and competitive antagonist of the D2-like receptors, specifically, dopamine receptor D2 (DRD2) and dopamine receptor D3 (DRD3) with a KD value of ~3 µM. The theme that dopamine and dopamine receptors are important in cancer has emerged in the literature. We hypothesize that ONC201’s interaction with DRD2 is critical for ONC201’s anticancer effects. Co-treating HCT116 and RKO colorectal cancer cells with ONC201 and dopamine or the selective D2-like receptor agonist sumanirole partially abrogated ONC201-induced ATF4/CHOP expression and apoptosis. Knocking down DRD2 expression using siRNA negated ONC201’s effects on viable cell count. Overexpressing DRD2 in a cancer cell line that has very low levels of DRD2, increased ONC201-induced PARP cleavage. Quantitative RT-PCR analyses showed that cells that have acquired resistance to ONC201 did not express detectable mRNA levels of the D2-like receptors. To further determine the anti-tumor potential of targeting the D2-like receptor, we treated different cancer cell lines with other D2-like receptor antagonists. Similar to ONC201, the D2-selective antagonist L-741,626 decreased cell viability and induced apoptosis in a number of cancer cell lines. In contrast to ONC201, however, L-741,626 has a poor therapeutic index. Our findings show that the ability of ONC201 to inhibit D2-like receptors contributes to ONC201’s antiproliferative and pro-apoptotic activity. Ongoing work is aimed at elucidating the mechanisms by which antagonism of D2-like receptors can promote apoptotic cell death, especially with regard to ATF4/CHOP/DR5 and Akt/ERK/Foxo3a/TRAIL, which have been shown to be stimulated in ONC201-treated and -sensitive tumor cells. Citation Format: Christina Leah B. Kline, Amriti Lulla, Jessica Wagner, David Dicker, Marie Baumeister, Sophie Oster, Wafik El-Deiry. Antagonism of D2-like dopamine receptors plays a role in Onc201’s anticancer effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3213. doi:10.1158/1538-7445.AM2017-3213