Wee1 inhibition triggers a GCN2-dependent integrated stress response

The Wee1 kinase controls cell cycle control through negative regulation of the CDK1 and CDK2 kinases to ensure proper DNA replication kinetics and prevent premature entry into mitosis. Conversely, pharmacological inhibition of WEE1 causes hyperactivation of CDK1 and CDK2, leading to premature mitosis in the presence of DNA lesions. Loss of TP53 and oncogene-mediated replication stress were previously described to confer Wee1 inhibitor sensitivity to tumor cells, although these tumor features do not invariably identify Wee1-inhibitor sensitive tumors.A genome-wide haploid insertional mutagenesis screen was performed to identify gene mutations that sensitize cells to Wee1 inhibition (Wee1i). Inactivation of the alternative translation initiation factor EIF2A was identified to sensitize cells to Wee1i.