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

Abstract

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.

Targeting Mitochondrial DNA Transcription by POLRMT Inhibition or Depletion as a Potential Strategy for Cancer Treatment

“…However, these results may depend on the specific ClpP agonist studied. For example, ONC201 treatment increased apoptosis in mantle cell lymphoma, AML, pancreatic ductal adenocarcinoma, multiple myeloma, and ovarian cancer cell lines, whereas there have been no reports of significant increases in apoptosis after TR compound treatment [ 77 , 79 , 80 , 81 , 82 ]. ONC201 was previously reported to be both a ClpP agonist and a dopamine receptor D2 antagonist, while the TR compounds are selective ClpP agonists [ 33 , 35 , 83 ], which may explain these differences.…”

ONC201/TIC10 enhances durability of mTOR inhibitor everolimus in metastatic ER+ breast cancer

“…In addition, CHOP can downregulate the expressions of Bcl-2, Bcl-xL, and Mcl-1, and upregulate the expression of BIM, causing increased BAK and BAX expression. Bcl-2, Bcl-xL, and Mcl-1 have been shown to be downregulated by imipridones and ONC201/TIC10 ( Al Madhoun et al, 2021 ; Rumman et al, 2021 ; Staley et al, 2021 ).…”