ArticleCancer research2014
EGFR-mediated chromatin condensation protects KRAS-mutant cancer cells against ionizing radiation.
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Article in Cancer research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 1 of them a synthesis that pooled it.
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41citing papers in PubMed, 1 pooled it
7.2field-weighted citation impact, top 2% of its field
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Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it, 65 citations in OpenAlex.
- Radiotherapy plus EGFR TKIs in non-small cell lung cancer patients with brain metastases: an update meta-analysis.Cancer medicine · 2016Pooled it
- Adding Erlotinib to Chemoradiation Improves Overall Survival but Not Progression-Free Survival in Stage III Non-Small Cell Lung Cancer.International journal of radiation oncology, biology, physics · 2015Trial
- Biomarkers of radioresistance in lung cancer: Current insights and future directions (Review).Molecular medicine reports · 2026Review
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- Targeting Monounsaturated Fatty Acid Metabolism for Radiosensitization of KRAS Mutant 3D Lung Cancer Models.Molecular cancer therapeutics · 2025Article
- Targeting the Hippo pathway to prevent radioresistance brain metastases from the lung (Review).International journal of oncology · 2024Review
- Differences in Radiosensitivity According to EGFR Mutation Status in Non-Small Cell Lung Cancer: A Clinical and In Vitro Study.Journal of personalized medicine · 2023Article
- Radio-resistance of hypoxic tumors: exploring the effects of oxygen and x-ray radiation on non-small lung cancer cell lines.Radiation oncology (London, England) · 2023Article
- Targeting K-Ras-mediated DNA damage response in radiation oncology: Current status, challenges and future perspectives.Clinical and translational radiation oncology · 2023Review
- Review: Mechanisms and perspective treatment of radioresistance in non-small cell lung cancer.Frontiers in immunology · 2023Review
- Review
- The Diverse Analysis Identifies MutatedWorld journal of oncology · 2022Article
- Review
- Screening and Validation of Molecular Targeted Radiosensitizers.International journal of radiation oncology, biology, physics · 2021Article
- KRAS mutation: from undruggable to druggable in cancer.Signal transduction and targeted therapy · 2021Review
- Oncogenic KRAS drives radioresistance through upregulation of NRF2-53BP1-mediated non-homologous end-joining repair.Nucleic acids research · 2021Article
- Lung cancer epidermal growth factor receptor mutations and radiotherapy response: A multicentre clinical study.Clinical and translational radiation oncology · 2021Article
- Prolonged cetuximab treatment promotes p27Scientific reports · 2021Article
- Article
- Targeting the DNA replication stress phenotype of KRAS mutant cancer cells.Scientific reports · 2021Article
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Authors and funding
13 authors at 8 institutions in 2 countries.
Meng WangAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ashley M KernAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Marieke HülskötterAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Patricia GreningerAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Anurag SinghAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Yunfeng PanAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Dipanjan ChowdhuryAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Mechthild KrauseAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, GermanyAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, GermanyAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical F
Michael BaumannAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, GermanyAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, GermanyAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical F
Cyril H BenesAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jason A EfstathiouAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jeff SettlemanAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Henning WillersAuthors' Affiliations: Department of Radiation Oncology, Massachusetts General Hospital; Center for Cancer Research, Massachusetts General Hospital Cancer Center; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden; and Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany hwillers@partners.org.
University Hospital Heidelberg · DEHeidelberg University · DEHelmholtz-Zentrum Dresden-Rossendorf · DEUniversity Hospital Carl Gustav Carus · DECenter for Cancer Research · USDana-Farber Cancer Institute · USGerman Cancer Research Center · DETU Dresden · DE
Funding
Translational studies of Hsp90 inhibitors in NSCLCP50CA090578 · NCI · DANA-FARBER CANCER INST · PI JOHNSON, BRUCE E. · 2008 to 2012
$11.4MMolecular mechanism and relevance of microRNAs in DSB repair pathway choiceR01CA142698 · NCI · DANA-FARBER CANCER INST · PI CHOWDHURY, DIPANJAN · 2010 to 2019
$3.8MDefining lineage-specific determinants of K-Ras "addiction" in human cancersK99CA149169 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI SINGH, ANURAG · 2010 to 2011
$268kPROTON THERAPY RESEARCH AND TREATMENT CENTERC06CA059267 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI GOITEIN, MICHAEL · 1992 to 1995
–NCI NIH HHS C06 CA059267NCI NIH HHS K99 CA149169NCI NIH HHS NCI P50 CA090578NCI NIH HHS NCI R01 CA142698NCI NIH HHS P50 CA090578NCI NIH HHS R01 CA142698Wellcome Trust 086357
Abstract
Therapeutics that target the epidermal growth factor receptor (EGFR) can enhance the cytotoxic effects of ionizing radiation (IR). However, predictive genomic biomarkers of this radiosensitization have remained elusive. By screening 40 non-small cell lung cancer cell (NSCLC) lines, we established a surprising positive correlation between the presence of a KRAS mutation and radiosensitization by the EGFR inhibitors erlotinib and cetuximab. EGFR signaling in KRAS-mutant NSCLC cells promotes chromatin condensation in vitro and in vivo, thereby restricting the number of DNA double-strand breaks (DSB) produced by a given dose of IR. Chromatin condensation in interphase cells is characterized by an unexpected mitosis-like colocalization of serine 10 phosphorylation and lysine 9 trimethylation on histone H3. Aurora B promotes this process in a manner that is codependent upon EGFR and protein kinase C α (PKCα). PKCα, in addition to MEK/ERK signaling, is required for the suppression of DSB-inducible premature senescence by EGFR. Blockade of autophagy results in a mutant KRAS-dependent senescence-to-apoptosis switch in cancer cells treated with IR and erlotinib. In conclusion, we identify EGFR as a molecular target to overcome a novel mechanism of radioresistance in KRAS-mutant tumor cells, which stands in contrast to the unresponsiveness of KRAS-mutant cancers to EGFR-directed agents in monotherapy. Our findings may reposition EGFR-targeted agents for combination with DSB-inducing therapies in KRAS-mutant NSCLC.
Indexed as
AnimalsApoptosisAurora Kinase BBenzimidazolesCarcinoma, Non-Small-Cell LungCell Line, TumorCellular SenescenceChromatinDNA Breaks, Double-StrandedErbB ReceptorsErlotinib HydrochlorideHumansLung NeoplasmsMiceMutationProtein Kinase C-alphaAURKB protein, humanAurora Kinase BAZD 6244BenzimidazolesChromatinErbB ReceptorsErlotinib HydrochlorideKRAS protein, humanProtein Kinase C-alphaProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)Quinazolinesras Proteins
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