Histone H3K36 trimethylation (H3K36me3) is frequently lost in multiple cancer types, identifying it as an important therapeutic target. Here we identify a synthetic lethal interaction in which H3K36me3-deficient cancers are acutely sensitive to WEE1 inhibition. We show that RRM2, a ribonucleotide reductase subunit, is the target of this synthetic lethal interaction. RRM2 is regulated by two pathways here: first, H3K36me3 facilitates RRM2 expression through transcription initiation factor recruitment; second, WEE1 inhibition degrades RRM2 through untimely CDK activation. Therefore, WEE1 inhibition in H3K36me3-deficient cells results in RRM2 reduction, critical dNTP depletion, S-phase arrest, and apoptosis. Accordingly, this synthetic lethality is suppressed by increasing RRM2 expression or inhibiting RRM2 degradation. Finally, we demonstrate that WEE1 inhibitor AZD1775 regresses H3K36me3-deficient tumor xenografts.
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Amino Acid Sequence, Animals, Base Sequence, Blotting, Western, Cell Cycle Proteins, Cell Line, Tumor, Cell Survival, Gene Expression Regulation, Neoplastic, Histone-Lysine N-Methyltransferase, Histones, Humans, Lysine, Methylation, Mice, Inbred BALB C, Mice, Nude, Molecular Sequence Data, Neoplasms, Nuclear Proteins, Nucleotides, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Pyrimidinones, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Ribonucleoside Diphosphate Reductase, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Xenograft Model Antitumor Assays