Targeting G2/M checkpoint vulnerability in homologous recombination-proficient tumors: lessons from ovarian cancer...

Cell cycle dysregulation is a hallmark of cancer; however, tumors retaining homologous recombination (HR)-proficiency remain a major challenge. Although PARP inhibitors effectively target HR-deficient cancers, targeted therapies for BRCA1/2-wild-type, HR-proficient tumors are limited. High-grade serous ovarian cancer, approximately half of which is HR-proficient, illustrates that HR proficiency, together with replication stress and checkpoint dependence, may represent both a mechanism of therapeutic resistance and a druggable dependency on checkpoint-coupled DNA repair. This review synthesizes evidence that targeting either PLK1 or WEE1 independently exposes this vulnerability. PLK1 and WEE1 inhibition engage distinct mechanisms: PLK1 inhibition disrupts spindle assembly and HR competence, whereas WEE1 inhibition amplifies replication stress and forces premature mitotic entry. Nevertheless, both ultimately converge to compromise HR-associated repair, promote unresolved DNA damage, and trigger lethal mitotic catastrophe. Finally, we discuss biomarker-unselected trial failures, functional and replication stress-based patient stratification, and rational combinations with DNA-damaging agents and immunotherapy.