Abstract 2792: The small molecule imipridone ONC201 is active in tumor types with dysregulation of the DRD2 pathway

Madhukar, Neel S.; Prabhu, Varun V.; Dardenne, Étienne; Doherty, Faye; VanEngelenburg, Alexander; Tarapore, Rohinton; Garnett, Mathew J.; McDermott, Ultan; Benes, Cyril H.; Oster, Wolfgang; El‐Deiry, Wafik S.; Stein, Mark N.; Rickman, David S.; Allen, Joshua E.; Elemento, Olivier

doi:10.1158/1538-7445.am2017-2792

Cited by 3 publications

(3 citation statements)

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“…DNA sequencing of ONC201-resistant RKO cells uncovered a missense mutation in dopamine receptor DRD5 [25] . Given that all of the cancer cell types tested in this study express DRD5 ( Table 1 ), we transiently knocked down DRD5 and assessed whether ONC201-induced anticancer activity would be increased.…”

Section: Resultsmentioning

confidence: 99%

Role of Dopamine Receptors in the Anticancer Activity of ONC201

et al. 2018

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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.

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Section: Resultsmentioning

confidence: 99%

Role of Dopamine Receptors in the Anticancer Activity of ONC201

et al. 2018

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“…ONC201 is a first‐in‐class small molecule selective orally bioavailable dopamine D2‐like receptor (DRD2) antagonist that is in Phase I‐II clinical trials in select cancers and has been well tolerated with minimal toxicity noted in these human trials 32–35 . Given ovarian cancer has >60% DRD2 surface expression it was felt that ONC201 would be an excellent candidate agent to study in this setting 19,25,33 .…”

Section: Discussionmentioning

confidence: 99%

ONC201 induces the unfolded protein response (UPR) in high‐ and low‐grade ovarian carcinoma cell lines and leads to cell death regardless of platinum sensitivity

et al. 2021

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ObjectivesTreatment of both platinum resistant high grade (HG) and low‐grade (LG) ovarian cancer (OVCA) poses significant challenges as neither respond well to conventional chemotherapy leading to morbidity and mortality. Identification of novel agents that can overcome chemoresistance is therefore critical. Previously, we have demonstrated that OVCA has basal upregulated unfolded protein response (UPR) and that targeting cellular processes leading to further and persistent upregulation of UPR leads to cell death. ONC201 is an orally bioavailable Dopamine Receptor D2 inhibitor demonstrating anticancer activity and was found to induce UPR. Given its unique properties, we hypothesized that ONC201 would overcome platinum resistance in OVCA.MethodsCisplatin sensitive and resistant HG OVCA and two primary LG OVCA cell lines were studied. Cell viability was determined using MTT assay. Cell migration was studied using wound healing assay. Apoptosis and mitochondrial membrane potential were investigated using flow cytometry. Analysis of pathway inhibition was performed by Western Blot. mRNA expression of UPR related genes were measured by qPCR. In vivo studies were completed utilizing axillary xenograft models. Co‐testing with conventional chemotherapy was performed to study synergy.ResultsONC201 significantly inhibited cell viability and migration in a dose dependent manner with IC50’s from 1‐20 µM for both cisplatin sensitive and resistant HG and LG‐OVCA cell lines. ONC201 lead to upregulation of the pro‐apoptotic arm of the UPR, specifically ATF‐4/CHOP/ATF3 and increased the intrinsic apoptosispathway. The compensatory, pro‐survival PI3K/AKT/mTOR pathway was downregulated. In vivo, weekly dosing of single agent ONC201 decreased xenograft tumor size by ~50% compared to vehicle. ONC201 also demonstrated significant synergy with paclitaxel in a highly platinum resistant OVCA cell‐line (OV433).ConclusionsOur findings demonstrate that ONC201 can effectively overcome chemoresistance in OVCA cells by blocking pro‐survival pathways and inducing the apoptotic arm of the UPR. This is a promising, orallybioavailable therapeutic agent to consider in clinical trials for patients with both HG and LG OVCA.

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“…He exhibited ibrutinib-refractory disease and experienced a transient anti-tumour effect after 3 cycles of ONC201. Since DRD5 mediates acquired and innate resistance to ONC201 through missense gain-of-function mutation and overexpression (Madhukar et al, 2017b), respectively, and our patient had DRD5-negative MCL, this could suggest an association with the initial response.…”

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confidence: 80%