Cyclin E1/CDK2 Activation Defines a Key Vulnerability to WEE1 Kinase Inhibition in Gynecological Cancers

Overview

Journal NPJ Precis Oncol

Publisher Springer Nature

Specialty Oncology

Date 2025 Jan 4

PMID 39755818

Authors

Daehwan Kim

Heekyung Chung

Wen Liu

Kangjin Jeong

Tugba Y Ozmen

Furkan Ozmen

Matthew J Rames

Sangyub Kim

Xiao Guo

Nathan Jameson

Petrus R de Jong

Steven Yea

Laurie Harford

Jiali Li

Cara A Mathews

Deborah B Doroshow

Vincent J Charles

Doris Kim

Kimberlee Fischer

Ahmed A Samatar

Adrian Jubb

Kevin D Bunker

Kimberly Blackwell

Fiona Simpkins

Funda Meric-Bernstam

Gordon B Mills

Olivier Harismendy

Jianhui Ma

Mark R Lackner

Affiliations

Soon will be listed here.

Abstract

Upregulation of Cyclin E1 and subsequent activation of CDK2 accelerates cell cycle progression from G1 to S phase and is a common oncogenic driver in gynecological malignancies. WEE1 kinase counteracts the effects of Cyclin E1/CDK2 activation by regulating multiple cell cycle checkpoints. Here we characterized the relationship between Cyclin E1/CDK2 activation and sensitivity to the selective WEE1 inhibitor azenosertib. We found that ovarian cancer cell lines with high levels of endogenous Cyclin E1 expression or forced overexpression were exquisitely sensitive to azenosertib and these results extended to in vivo models of ovarian and uterine serous carcinoma. Models with high Cyclin E1 expression showed higher baseline levels of replication stress and enhanced cellular responses to azenosertib treatment. We found azenosertib synergized with different classes of chemotherapy and described distinct underlying mechanisms. Finally, we provided early evidence from an ongoing phase I study demonstrating the clinical activity of monotherapy azenosertib in patients with Cyclin E1/CDK2-activated ovarian and uterine serous carcinomas.

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