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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

Open Access 01-12-2021 | Endometrial Cancer | Research

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

Authors: Stuart R. Pierce, Ziwei Fang, Yajie Yin, Lindsay West, Majdouline Asher, Tianran Hao, Xin Zhang, Katherine Tucker, Allison Staley, Yali Fan, Wenchuan Sun, Dominic T. Moore, Chang Xu, Yi-Hsuan Tsai, Joel Parker, Varun Vijay Prabhu, Joshua E. Allen, Douglas Lee, Chunxiao Zhou, Victoria Bae-Jump

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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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.
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Metadata
Title
Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer
Authors
Stuart R. Pierce
Ziwei Fang
Yajie Yin
Lindsay West
Majdouline Asher
Tianran Hao
Xin Zhang
Katherine Tucker
Allison Staley
Yali Fan
Wenchuan Sun
Dominic T. Moore
Chang Xu
Yi-Hsuan Tsai
Joel Parker
Varun Vijay Prabhu
Joshua E. Allen
Douglas Lee
Chunxiao Zhou
Victoria Bae-Jump
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-01842-9

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