Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation

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 re...

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Published in:Cancer cell Vol. 28; no. 5; pp. 557 - 568
Main Authors: Pfister, Sophia X, Markkanen, Enni, Jiang, Yanyan, Sarkar, Sovan, Woodcock, Mick, Orlando, Giulia, Mavrommati, Ioanna, Pai, Chen-Chun, Zalmas, Lykourgos-Panagiotis, Drobnitzky, Neele, Dianov, Grigory L, Verrill, Clare, Macaulay, Valentine M, Ying, Songmin, La Thangue, Nicholas B, D'Angiolella, Vincenzo, Ryan, Anderson J, Humphrey, Timothy C
Format: Journal Article
Language:English
Published: United States 09.11.2015
Subjects:
Amino Acid Sequence
Animals
Base Sequence
Blotting, Western
Cell Cycle Proteins - antagonists & inhibitors
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line, Tumor
Cell Survival - drug effects
Cell Survival - genetics
Gene Expression Regulation, Neoplastic - drug effects
Histone-Lysine N-Methyltransferase - genetics
Histone-Lysine N-Methyltransferase - metabolism
Histones - genetics
Histones - metabolism
Humans
Lysine - genetics
Lysine - metabolism
Methylation - drug effects
Mice, Inbred BALB C
Mice, Nude
Molecular Sequence Data
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - prevention & control
Nuclear Proteins - antagonists & inhibitors
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Nucleotides - genetics
Nucleotides - metabolism
Protein-Tyrosine Kinases - antagonists & inhibitors
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - metabolism
Pyrazoles - pharmacology
Pyrimidines - pharmacology
Pyrimidinones
Reverse Transcriptase Polymerase Chain Reaction
Ribonucleoside Diphosphate Reductase - genetics
Ribonucleoside Diphosphate Reductase - metabolism
RNA Interference
Sequence Homology, Amino Acid
Sequence Homology, Nucleic Acid
Xenograft Model Antitumor Assays
ISSN:1878-3686
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Summary: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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ISSN:1878-3686
DOI:10.1016/j.ccell.2015.09.015