title: Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation.
abstract: 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.
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Sophia X
authors.initials: SX
authors.lastname: Pfister
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; Institute of Pharmacology and Toxicology, Vetsuisse Faculty, Winterthurerstrasse 260, 8057 Zürich, Switzerland.
authors.forename: Enni
authors.initials: E
authors.lastname: Markkanen
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Sovan
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Mick
authors.initials: M
authors.lastname: Woodcock
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Giulia
authors.initials: G
authors.lastname: Orlando
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Mavrommati
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Chen-Chun
authors.initials: CC
authors.lastname: Pai
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Lykourgos-Panagiotis
authors.initials: LP
authors.lastname: Zalmas
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Neele
authors.initials: N
authors.lastname: Drobnitzky
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; Institute of Cytology and Genetics RAS, Novosibirsk 630090, Russia.
authors.forename: Grigory L
authors.initials: GL
authors.lastname: Dianov
authors.affiliation: Department of Cellular Pathology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Verrill
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK; Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Valentine M
authors.initials: VM
authors.lastname: Macaulay
authors.affiliation: Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital and Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Songmin
authors.initials: S
authors.lastname: Ying
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: La Thangue
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: D'Angiolella
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ryan
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: timothy.humphrey@oncology.ox.ac.uk.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Humphrey
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009711:Nucleotides / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011744:Pyrimidinones; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D006657:Histones; D009687:Nuclear Proteins; D009711:Nucleotides; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C549567:adavosertib; D008239:Lysine