G2/M Checkpoint Dependency in High-Grade Serous Tubo-Ovarian Carcinoma: Mechanisms and Therapeutic Implications.

High-grade serous carcinoma (HGSC) of tubo-ovarian origin is an aggressive malignancy in need of new treatment options. At the molecular level, HGSC is characterized by genomic instability, including nearly universal TP53 mutations, copy number alterations, and chromothripsis, which elevate replication stress. These fundamental alterations result in tumor cell dependence on the G2/M checkpoint for survival, thus revealing this checkpoint as a potential therapeutic target. In this review, we discuss the normal cell cycle progression and checkpoints as well as the regulation of DNA replication, and we consider how replication stress in HGSC leads to a dependence on the G2/M checkpoint. We then present information on the current state of targeted therapy development for HGSC including clinical trials and the role of biomarkers in optimal patient selection. Thus, targeting the G2/M checkpoint is driven by sound molecular rationale and may yield clinical benefit in patients with HGSC, but will likely require careful patient selection and consideration of treatment toxicities.