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 |
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| Main Authors: | , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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United States
09.11.2015
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| ISSN: | 1878-3686 |
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| 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. |
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| AbstractList | 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. |
| Author | Sarkar, Sovan D'Angiolella, Vincenzo Pai, Chen-Chun Ryan, Anderson J Verrill, Clare Jiang, Yanyan Mavrommati, Ioanna Ying, Songmin Humphrey, Timothy C Woodcock, Mick Orlando, Giulia Pfister, Sophia X La Thangue, Nicholas B Dianov, Grigory L Drobnitzky, Neele Macaulay, Valentine M Markkanen, Enni Zalmas, Lykourgos-Panagiotis |
| Author_xml | – sequence: 1 givenname: Sophia X surname: Pfister fullname: Pfister, Sophia X organization: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 2 givenname: Enni surname: Markkanen fullname: Markkanen, Enni organization: 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 – sequence: 3 givenname: Yanyan surname: Jiang fullname: Jiang, Yanyan organization: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 4 givenname: Sovan surname: Sarkar fullname: Sarkar, Sovan organization: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 5 givenname: Mick surname: Woodcock fullname: Woodcock, Mick organization: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 6 givenname: Giulia surname: Orlando fullname: Orlando, Giulia organization: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 7 givenname: Ioanna surname: Mavrommati fullname: Mavrommati, Ioanna organization: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 8 givenname: Chen-Chun surname: Pai fullname: Pai, Chen-Chun organization: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 9 givenname: Lykourgos-Panagiotis surname: Zalmas fullname: Zalmas, Lykourgos-Panagiotis organization: Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK – sequence: 10 givenname: Neele surname: Drobnitzky fullname: Drobnitzky, Neele organization: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 11 givenname: Grigory L surname: Dianov fullname: Dianov, Grigory L organization: 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 – sequence: 12 givenname: Clare surname: Verrill fullname: Verrill, Clare organization: Department of Cellular Pathology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK – sequence: 13 givenname: Valentine M surname: Macaulay fullname: Macaulay, Valentine M organization: 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 – sequence: 14 givenname: Songmin surname: Ying fullname: Ying, Songmin organization: Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital and Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China – sequence: 15 givenname: Nicholas B surname: La Thangue fullname: La Thangue, Nicholas B organization: Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK – sequence: 16 givenname: Vincenzo surname: D'Angiolella fullname: D'Angiolella, Vincenzo organization: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 17 givenname: Anderson J surname: Ryan fullname: Ryan, Anderson J organization: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 18 givenname: Timothy C surname: Humphrey fullname: Humphrey, Timothy C email: timothy.humphrey@oncology.ox.ac.uk organization: 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 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26602815$$D View this record in MEDLINE/PubMed |
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| Snippet | Histone H3K36 trimethylation (H3K36me3) is frequently lost in multiple cancer types, identifying it as an important therapeutic target. Here we identify a... |
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| SubjectTerms | 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 |
| Title | Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation |
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