Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.ccell.2015.09.015

Type

Journal article

Journal

Cancer Cell

Publication Date

09/11/2015

Volume

28

Pages

557 - 568

Keywords

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