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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Vydané v:	Cancer cell Ročník 28; číslo 5; s. 557 - 568
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 09.11.2015
Predmet:	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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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1878-3686
DOI:	10.1016/j.ccell.2015.09.015