CDK2 regulates collapsed replication fork repair in CCNE1-amplified ovarian cancer cells via homologous recombination

Author:

Brown Victoria E12ORCID,Moore Sydney L12,Chen Maxine1,House Nealia1ORCID,Ramsden Philip1,Wu Hsin-Jung1,Ribich Scott1,Grassian Alexandra R1,Choi Yoon Jong1

Affiliation:

1. Blueprint Medicines , Cambridge , MA 02139, USA

2. Department of Biology, Tufts University , Medford , MA 02155, USA

Abstract

Abstract CCNE1 amplification is a common alteration in high-grade serous ovarian cancer and occurs in 15–20% of these tumors. These amplifications are mutually exclusive with homologous recombination deficiency, and, as they have intact homologous recombination, are intrinsically resistant to poly (ADP-ribose) polymerase inhibitors or chemotherapy agents. Understanding the molecular mechanisms that lead to this mutual exclusivity may reveal therapeutic vulnerabilities that could be leveraged in the clinic in this still underserved patient population. Here, we demonstrate that CCNE1-amplified high-grade serous ovarian cancer cells rely on homologous recombination to repair collapsed replication forks. Cyclin-dependent kinase 2, the canonical partner of cyclin E1, uniquely regulates homologous recombination in this genetic context, and as such cyclin-dependent kinase 2 inhibition synergizes with DNA damaging agents in vitro and in vivo. We demonstrate that combining a selective cyclin-dependent kinase 2 inhibitor with a DNA damaging agent could be a powerful tool in the clinic for high-grade serous ovarian cancer.

Funder

Blueprint Medicines

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets;International Journal of Molecular Sciences;2024-01-19

2. Cancer takes many paths through G1/S;Trends in Cell Biology;2023-11

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