Evidence map›Paper›PMID 26602815›Full record

ArticleCancer cell2015

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

Sophia X Pfister, Enni Markkanen, Yanyan Jiang, Sovan Sarkar, Mick Woodcock, Giulia Orlando, Ioanna Mavrommati, Chen-Chun Pai, Lykourgos-Panagiotis Zalmas, Neele Drobnitzky and 8 more

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In one paragraph

Article in Cancer cell, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 194 papers.

0numbers the graph read from it
0cells of the map it votes in
194citing papers in PubMed
14.5field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

194 citing papers in PubMed, 305 citations in OpenAlex.

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  20. Targeting WEE1 Kinase for Breast Cancer Therapeutics: An Update.International journal of molecular sciences · 2025
    Review

134 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

18 authors at 6 institutions in 4 countries.

Sophia X PfisterCRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Enni MarkkanenCRUK 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.
Yanyan JiangCRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Sovan SarkarCRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Mick WoodcockCRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Giulia OrlandoCRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Ioanna MavrommatiCRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Chen-Chun PaiCRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Lykourgos-Panagiotis ZalmasDepartment of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
Neele DrobnitzkyCRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Grigory L DianovCRUK 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.
Clare VerrillDepartment of Cellular Pathology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Valentine M MacaulayDepartment 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.
Songmin YingDepartment of Respiratory and Critical Care Medicine of the Second Affiliated Hospital and Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Nicholas B La ThangueDepartment of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
Vincenzo D'AngiolellaCRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Anderson J RyanCRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Timothy C HumphreyCRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: timothy.humphrey@oncology.ox.ac.uk.
University of Oxford · GBCRUK/MRC Oxford Institute for Radiation Oncology · GBChurchill Hospital · GBJohn Radcliffe Hospital · GBSecond Affiliated Hospital of Zhejiang University · CNUniversity of Zurich · CH

Funding

Cancer Research UK 13058Medical Research Council G0500905Medical Research Council G1000807Medical Research Council G9400953Medical Research Council MC_PC_12001Medical Research Council MC_PC_12002Medical Research Council MC_PC_12003Medical Research Council MC_PC_12006
6 · The paper itself

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.

Indexed as

Amino Acid SequenceAnimalsBase SequenceBlotting, WesternCell Cycle ProteinsCell Line, TumorCell SurvivalGene Expression Regulation, NeoplasticHistone-Lysine N-MethyltransferaseHistonesHumansLysineMethylationMice, Inbred BALB CMice, NudeMolecular Sequence DataadavosertibCell Cycle ProteinsHistone-Lysine N-MethyltransferaseHistonesLysineNuclear ProteinsNucleotidesProtein-Tyrosine KinasesPyrazolesPyrimidinesPyrimidinonesRibonucleoside Diphosphate Reductaseribonucleotide reductase M2SETD2 protein, humanWEE1 protein, human

Identifiers

PMID26602815
PMCPMC4643307
OpenAlexW2181205541

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.