ONC206, an Imipridone Derivative, Induces Cell Death Through Activation of the Integrated Stress Response in Serous Endometrial Cancer In Vitro.

Yingao Zhang,Allison Staley,Yu Huang,Chunxiao Zhou,Joshua E Allen,Yajie Yin,Katherine Tucker,Yali Fan,Wenchuan Sun,Sarah Paraghamian,Victoria Bae-Jump,Xiaoling Zhao,Varun Prabhu,Gabrielle Hawkins

doi:10.3389/fonc.2020.577141

Abstract

ONC206 (Oncoceutics) is an imipiridone with nanomolar potency and analogue of ONC201, a selective dopamine receptor D2 (DRD2) antagonist currently being investigated in phase II clinical trials for serous endometrial cancer (SEC). This study investigated the anti-proliferative efficacy of ONC206 in SEC cell lines as well as its impact on cellular stress and adhesion/invasion. ONC206 inhibited cellular proliferation in a dose-dependent manner and was more potent than ONC201 in the ARK1 (IC50 = 0.33µM vs. IC50 = 1.59uM) and SPEC-2 (IC50 = 0.24uM vs. IC50 = 0.81uM) cell lines. Treatment with ONC206 resulted in induction of ROS production and reduction of mitochondrial membrane potential, accompanied by an increase in cleaved caspase-3 and caspase-9 activity (p < 0.01). ONC206 also significantly inhibited cellular adhesion and migration in both cell lines (p < 0.01). Pretreatment with the stress inhibitor N-acetylcysteine (NAC) significantly attenuated the efficacy of ONC206 on cell proliferation, ROS production and cellular invasion. ONC206 demonstrates nanomolar potency for the inhibition of proliferation in SEC cells. Specifically, ONC206 utilizes ISR activation as a significant pathway in the propagation of its anti-proliferative and anti-metastatic effects. Thus, ONC206 may be a promising agent in future SEC clinical trials as was its predecessor ONC201.

Highlights

With over 65,000 new cases estimated in 2020, endometrial cancer (EC) remains the most common gynecologic malignancy in the United States [1]
As our group had previously shown that ONC201 inhibited proliferation in serous endometrial cancer (SEC) cell lines [13], the aim of this study was to expand on this work and evaluate the effect of ONC206 on cell proliferation, cellular stress, migration, and invasion in SEC cells
The SEC cell lines, ARK1 and SPEC-2, were cultured in medium with various concentrations of ONC201 or ONC206 for 72 h and cellular viability was analyzed with the MTT assay

Summary

Introduction

With over 65,000 new cases estimated in 2020, endometrial cancer (EC) remains the most common gynecologic malignancy in the United States [1]. Within these cancers, 80%–90% have an endometrioid adenocarcinoma histology and are classified as type I ECs. Type II ECs encompass all other histological subtypes (i.e., serous, clear cell, and carcinosarcoma); less prevalent, these tumors behave much more aggressively in terms of disease progression and recurrence rates after treatment [2]. Reported 5-year survival rates for SECs are dismal, ranging from 30% to 55% [3, 5, 7], compared to 75% for women with high grade endometrioid tumors and >90% for low grade endometrioid tumors [7,8,9]. This highlights a continuing need to explore novel therapeutic strategies for SEC, an especially deadly histology of EC [10]

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Conclusion