WEE1 inhibition in cancer therapy: Mechanisms, synergies, preclinical insights, and clinical trials

Abstract

WEE1 is a serine/threonine kinase that regulates the G2/M checkpoint by phosphorylating CDK1, preventing premature mitotic entry and maintaining genomic stability. Many cancers, particularly those with TP53 mutations, upregulate WEE1 to counteract replication stress and DNA damage, making it a key target for therapy. WEE1 inhibitors, especially adavosertib (AZD1775), have shown strong preclinical and clinical activity in ovarian, breast, gastrointestinal, and head and neck cancers. By inducing mitotic catastrophe and increasing DNA damage, WEE1 inhibition enhances the effectiveness of chemotherapies, including platinum-based agents, antimetabolites, and PARP inhibitors. It also synergizes with radiotherapy and immune checkpoint inhibitors, improving responses in tumors with immune evasion. However, challenges such as acquired resistance, toxicity, and patient selection remain obstacles to clinical implementation. Given the expanding role of WEE1 inhibitors in cancer treatment, a comprehensive review is needed to summarize their biological functions, structural regulation, and therapeutic applications. This review highlights key findings from preclinical and clinical studies, explores emerging biomarkers for patient stratification, and discusses strategies to overcome resistance and toxicity. By integrating current knowledge, we aim to provide insights into optimizing WEE1-targeted therapies and guiding future research to maximize their clinical impact in cancer treatment.