Inhibition of CDK1 by RO-3306 Exhibits Anti-Tumorigenic Effects in Ovarian Cancer Cells and a Transgenic Mouse Model of Ovarian Cancer

Author:

Huang Yu12ORCID,Fan Yali23,Zhao Ziyi23,Zhang Xin23,Tucker Katherine2,Staley Allison2,Suo Hongyan23,Sun Wenchuan2,Shen Xiaochang23,Deng Boer23,Pierce Stuart R.2,West Lindsay2,Yin Yajie2,Emanuele Michael J.45,Zhou Chunxiao25,Bae-Jump Victoria25

Affiliation:

1. Department of Gynecologic Oncology, Chongqing University Cancer Hospital, Chongqing 400044, China

2. Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

3. Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100054, China

4. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

5. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

Abstract

Ovarian cancer is the deadliest gynecological malignancy of the reproductive organs in the United States. Cyclin-dependent kinase 1 (CDK1) is an important cell cycle regulatory protein that specifically controls the G2/M phase transition of the cell cycle. RO-3306 is a selective, ATP-competitive, and cell-permeable CDK1 inhibitor that shows potent anti-tumor activity in multiple pre-clinical models. In this study, we investigated the effect of CDK1 expression on the prognosis of patients with ovarian cancer and the anti-tumorigenic effect of RO-3306 in both ovarian cancer cell lines and a genetically engineered mouse model of high-grade serous ovarian cancer (KpB model). In 147 patients with epithelial ovarian cancer, the overexpression of CDK1 was significantly associated with poor prognosis compared with a low expression group. RO-3306 significantly inhibited cellular proliferation, induced apoptosis, caused cellular stress, and reduced cell migration. The treatment of KpB mice with RO-3306 for four weeks showed a significant decrease in tumor weight under obese and lean conditions without obvious side effects. Overall, our results demonstrate that the inhibition of CDK1 activity by RO-3306 effectively reduces cell proliferation and tumor growth, providing biological evidence for future clinical trials of CDK1 inhibitors in ovarian cancer.

Funder

UNC University Cancer Research Fund

National Institutes of Health

America Cancer Society

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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