WEE1 as a checkpoint regulator and therapeutic vulnerability: From biology to clinical development

Abstract

WEE1 is a critical cell-cycle checkpoint kinase that inhibits cyclin-dependent kinase activity via phosphorylation, coordinating DNA replication, repair, and mitotic entry. Although primarily recognized for its canonical function at the G2/M checkpoint, WEE1 also modulates S-phase dynamics by preventing unscheduled origin firing and stabilizing replication forks during replication stress. Tumors characterized by heightened replication stress, baseline DNA damage, and defective G1/S control (such as TP53 mutations or CCNE1 amplification) often exhibit a profound dependency on WEE1 for survival. This synthetic lethality has driven the clinical development of WEE1 inhibitors, including adavosertib and various next-generation agents, for use as monotherapies and combinatorial regimens. This review discusses the structure and regulation of WEE1, its functions in checkpoint control and stress responses, and the oncogenic consequences of its dysregulation. Furthermore, we summarize the clinical landscape of WEE1 inhibitors, highlighting strategies for biomarker-driven patient selection and therapeutic schedule optimization.