Wee1-like protein kinase (WEE1) (WEE1)

Wee1-like protein kinase (WEE1) is a critical nuclear kinase that regulates the G2/M cell cycle checkpoint by phosphorylating and inactivating the CDK1/Cyclin B complex [UniProt P30291]. This regulatory mechanism prevents cells from entering mitosis prematurely, providing a window for the repair of damaged DNA [PubMed: 28473494]. In the presence of gemcitabine-induced genotoxic stress, which causes replication fork stalling and DNA double-strand breaks, WEE1 activity becomes a vital survival signal for cancer cells to avoid lethal mitotic entry [PubMed: 22430223]. Therapeutic inhibition of WEE1, using agents like adavosertib, abrogates this checkpoint and forces cells into mitotic catastrophe, a strategy that is particularly effective in TP53-mutant tumors that lack a functional G1 checkpoint [NCI Drug Dictionary]. This combination therapy exploits the synthetic lethality between DNA-damaging agents and checkpoint inhibition to selectively eliminate malignant cells [PubMed: 30104349].

Other names

WEE1 kinaseWEE1huWee1 checkpoint kinaseDual specificity tyrosine-phosphorylation kinase WEE1

WEE1 inhibitors block the phosphorylation of CDK1 (CDC2) at Tyr15, which prevents the inactivation of the CDK1/Cyclin B complex. This forces cells to bypass the G2/M checkpoint and enter mitosis prematurely, leading to mitotic catastrophe in cells with existing DNA damage [PubMed: 21472142].