Treatment for ovarian clear cell carcinoma with combined inhibition of WEE1 and ATR

Sep 24, 2026

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Standard platinum-based therapy shows limited effectiveness against ovarian clear cell carcinoma (OCCC), a distinct epithelial subtype with frequent ARID1A inactivation and notable occurrence in East Asia. This study screened 166 compounds, including FDA-approved and clinical/preclinical agents, to identify candidate drugs. ARID1A knockdown cells were more sensitive to mTOR, dual mTOR/PI3K, ATR and MDM2 inhibitors, while BH3-domain and SRC targeting compounds showed preferential cytotoxicity in ARID1A mutant lines.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Background

OCCC response limitations and prognosis

Results

High-throughput screening of 166 compounds

Differential sensitivity in ARID1A mutant models

Conclusions

Cytotoxicity of ATR and WEE1 inhibition candidates

Chien et al. Journal of Ovarian Research (2023) 16:80 [https://doi.org/10.1186/s13048-023-01160-y](https://doi.org/10.1186/s13048-023-01160-y) Journal of Ovarian Research RESEARCH Open Access Treatment for ovarian clear cell carcinoma with combined inhibition of WEE1 and ATR Wenwen Chien1*, Jeffrey W. Tyner2, Sigal Gery1, Yueyuan Zheng3, Li-Yan Li4, Mohan Shankar Gopinatha Pillai 1, Chehyun Nam5, Neil A. Bhowmick 1, De-Chen Lin5 and H. Phillip Koeffler1,6 Abstract Background Standard platinum-based therapy for ovarian cancer is inefficient against ovarian clear cell carcinoma (OCCC) . OCCC is a distinct subtype of epithelial ovarian cancer. OCCC constitutes 25% of ovarian cancers in East Asia (Japan, Korea, China, Singapore) and 6–10% in Europe and North America. The cancer is characterized by frequent inactivation of ARID1A and 10% of cases of endometriosis progression to OCCC. The aim of this study was to identify drugs that are either FDA-approved or in clinical trials for the treatment of OCCC. Results High throughput screening of 166 compounds that are either FDA-approved, in clinical trials or are in preclinical studies identified several cytotoxic compounds against OCCC. ARID1A knockdown cells were more sensitive to inhibitors of either mTOR (PP242), dual mTOR/PI3K (GDC0941), ATR (AZD6738) or MDM2 (RG7388) compared to control cells. Also, compounds targeting BH3 domain (AZD4320) and SRC (AZD0530) displayed preferential cytotoxicity against ARID1A mutant cell lines. In addition, WEE1 inhibitor (AZD1775) showed broad cytotoxicity toward OCCC cell lines, irrespective of ARID1A status. Conclusions In a selection of 166 compounds we showed that inhibitors of ATR and WEE1 were cytotoxic against a panel of OCCC cell lines. These two drugs are already in other clinical trials, making them ideal candidates for treatment of OCCC. Keywords Ovarian clear cell carcinoma, ATR, WEE1 *Correspondence: Wenwen Chien [chienw1@cshs.org](chienw1@cshs.org) 1Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA 2Knight Cancer Institute, Oregon Health & Science University, Oregon Health and Science University, 2720 S.W. Moody Avenue, Portland, OR 97201, USA 3Clinical Big Data Research Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, P. R. China 4The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guandong Province, P. R. China 5Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90089, USA 6Department of Hematology-Oncology, National University Cancer Institute of Singapore, National University Hospital, Singapore 119074, Singapore Background Ovarian clear cell carcinoma (OCCC) patients show low response rates (10–25%) to standard ovarian cancer therapy (carboplatin and paclitaxel). This therapy is effective (~ 80% response rate) in other subtypes (high-grade serous, endometrioid) of ovarian cancer [1, 2]. When adjusted for stage, OCCC has the worst prognosis [3]. Moreover, patients with either late stage or progressive disease of OCCC have poor 5-year survival rate (13%) [4]. OCCC constitutes ~ 6% of ovarian cancer in North America and Europe [3] and has high prevalence (25%) in East Asia (Japan, Korea, China, Singapore) [5–7]. The most frequently mutated gene in OCCC is ARID1A (AT-rich interactive domain-containing protein 1 A) © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or o

FAQs

Why is standard platinum therapy less effective for ovarian clear cell carcinoma (OCCC)?

OCCC patients show low response rates to carboplatin and paclitaxel compared with other ovarian cancer subtypes. The document also notes a worse prognosis, particularly when adjusted for stage.

What was the goal of the study on OCCC treatment?

The study aimed to identify drugs that are either FDA-approved or in clinical trials for treating OCCC, using high-throughput screening across a 166-compound panel.

Which inhibitors showed cytotoxic effects against OCCC cell lines?

Inhibitors of ATR and WEE1 were shown to be cytotoxic across a panel of OCCC cell lines. The study also reports additional sensitivities to mTOR, dual mTOR/PI3K, and MDM2 inhibitors, with preferential effects for BH3-domain and SRC targeting compounds in ARID1A mutant lines.

Sep 24, 2026

Uploaded by Noah