title: EGFR-mediated chromatin condensation protects KRAS-mutant cancer cells against ionizing radiation.
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.
authors.affiliation: Authors' 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.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Authors' 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.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Kern
authors.affiliation: Authors' 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.
authors.forename: Marieke
authors.initials: M
authors.lastname: Hülskötter
authors.affiliation: Authors' 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.
authors.forename: Patricia
authors.initials: P
authors.lastname: Greninger
authors.affiliation: Authors' 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.
authors.forename: Anurag
authors.initials: A
authors.lastname: Singh
authors.affiliation: Authors' 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.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Authors' 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.
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chowdhury
authors.affiliation: Authors' 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
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.affiliation: Authors' 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
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Authors' 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.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Authors' 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.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Efstathiou
authors.affiliation: Authors' 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.
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
authors.affiliation: Authors' 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.
authors.forename: Henning
authors.initials: H
authors.lastname: Willers
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064107:Aurora Kinase B / Q000235:genetics / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D051379:Mice; D009154:Mutation; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D002843:Chromatin; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C576921:AURKB protein, human; D064107:Aurora Kinase B; D051571:Protein Kinase C-alpha; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins