Research Papers:

Loss of ARID1A expression leads to sensitivity to ROS-inducing agent elesclomol in gynecologic cancer cells

Suet-Yan Kwan _, Xuanjin Cheng, Yvonne T.M. Tsang, Jong-Sun Choi, Suet-Ying Kwan, Daisy I. Izaguirre, Hoi-Shan Kwan, David M. Gershenson and Kwong-Kwok Wong

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Oncotarget. 2016; 7:56933-56943. https://doi.org/10.18632/oncotarget.10921

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Suet-Yan Kwan1,2, Xuanjin Cheng3, Yvonne T.M. Tsang1, Jong-Sun Choi1,4, Suet-Ying Kwan1,2, Daisy I. Izaguirre1,2, Hoi-Shan Kwan3, David M. Gershenson1, Kwong-Kwok Wong1,2

1Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

2Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

3School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

4The Center for Anti-cancer Companion Diagnostics, Institutes of Entrepreneurial BioConvergence, Seoul National University, Gwanak-Gu, Seoul, Korea

Correspondence to:

Kwong-Kwok Wong, email: kkwong@mdanderson.org

Keywords: ARID1A, reactive oxygen species, elesclomol, ovarian cancer, drug sensitivity

Received: December 04, 2015    Accepted: July 18, 2016    Published: July 29, 2016


Inactivating mutations in ARID1A are found in a broad spectrum of cancer types, with the highest frequency in gynecologic cancers. However, therapeutic strategies targeting ARID1A-mutant cancer cells remain limited. In this study, we aimed to identify drugs sensitivities in ARID1A-mutant cancer cell lines. By analyzing the Genomics of Drug Sensitivity in Cancer database, we found that ARID1A-mutant cancer cell lines were more sensitive to treatment with the reactive oxygen species (ROS)-inducing agent elesclomol. In a panel of 14 gynecologic cancer cell lines, treatment with elesclomol inhibited growth and induced apoptosis more potently in ARID1A-mutant cells. Knockdown of ARID1A in RMG1 and OVCA432 ovarian cancer cells resulted in increased sensitivity to elesclomol, whereas restoration of ARID1A expression in TOV21G ovarian cancer cells resulted in increased resistance to elesclomol. Furthermore, we found that knockdown of ARID1A expression resulted in increased intracellular ROS levels. In ovarian clear cell carcinoma patient samples, low expression of ARID1A correlated with high expression of 8-hydroxyguanosine, a marker for oxidative stress. In summary, we demonstrate for the first time that loss of ARID1A leads to accumulation of ROS and suggest that elesclomol may be used to target ARID1A-mutant gynecologic cancer cells.

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