Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

Abstract

Background ONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer. Methods Cell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer. Results Increasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice. Conclusion ONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer

“…DRD2 Inhibition through genetic or pharmacological approaches has been shown to cause apoptosis and induce cell cycle arrest in leukemia, lung, colon, breast, endometrial, cervical, ovarian, pancreatic and brain cancer cells ( 11 , 12 , 35 – 40 ). ONC201 has recently been shown to induce apoptosis via targeting DRD2 in a wide variety of different cancer types.…”

“…Pre-clinical studies have shown that ONC201 presents anti-tumorigenic effects in dopamine pathway-dysregulated solid tumors and hematologic malignancies ( 5 , 9 , 10 ). We recently found that ONC201 exhibited anti-tumorigenic and anti-metastatic activity in uterine serous carcinoma (USC) in vitro and inhibited tumor growth in a transgenic mouse model of endometrial cancer under obese and lean conditions ( 11 , 12 ). Phase I clinical trials revealed that ONC201 is clinically active and exceptionally well-tolerated with favorable pharmacokinetics and pharmacodynamics in a variety of cancers, including lymphoma, glioblastoma and endometrial cancer ( 4 , 11 , 13 – 16 ).…”

Systematic Analysis of Neurotransmitter Receptors in Human Breast Cancer Reveals a Strong Association With Outcome and Uncovers HTR6 as a Survival-Associated Gene Potentially Regulating the Immune Microenvironment

“…However, the molecules mediating the potential carcinogenicity of psychiatric drugs remain poorly understood. Neurotransmitter receptors, as frequent targets of psychiatric drugs, have been uncovered being relevant to tumorigenesis (13)(14)(15)(16)(17)(18)(19). Therefore, we hypothesized that the potential oncogenicity of psychotic drugs might be mediated by their targeted neurotransmitter receptors.…”

“…(12). Recent research has provided clues that genes commonly targeted by psychiatric drugs (neurotransmitter receptors) may play a role in the development of cancer (13)(14)(15)(16)(17)(18)(19), implying the potential oncogenic properties of antipsychotics may be related to the activity changes of these neurotransmitter receptors after drug administration. However, there are still very few studies disclosing the functions of neurotransmitter receptors in tumorigenesis.…”

Exploring the Molecular Mechanism of Astragali Radix-Curcumae Rhizoma against Gastric Intraepithelial Neoplasia by Network Pharmacology and Molecular Docking

“…Previous studies suggested that dopamine receptor D2 (DRD2) expression can be used to evaluate the prognosis of patients with gastric or esophageal cancer [49,50]. Moreover, targeting DRD2 has been a novel therapeutic strategy in tumor-related diseases [51][52][53]. us, DRD2 may play an important role in GC.…”