Adavosertib and beyond: Biomarkers, drug combination and toxicity of WEE1 inhibitors

WEE1 kinase is renowned as an S-G2 checkpoint inhibitor activated by ATR-CHK1 in response to replication stress. WEE1 inhibition enhances replication stress and effectively circumvents checkpoints into mitosis, which triggers significant genetic impairs and culminates in cell death. This approach has been validated clinically for its promising anti-tumor efficacy across various cancer types, notably in cases of ovarian cancers. Nonetheless, the initial stage of clinical trials has shown that the first-in-human WEE1 inhibitor adavosertib is limited by dose-limiting adverse events. As a result, recent efforts have been made to explore predictive biomarkers and smart combination schedules to alleviate adverse effects. In this review, we focused on the exploration of therapeutic biomarkers, as well as schedules of combination utilizing WEE1 inhibitors and canonical anticancer drugs, according to the latest preclinical and clinical studies, indicating that the optimal application of WEE1 inhibitors will likely be as part of dose-reducing combination and be tailored to specific patient populations.