Format

Send to

Choose Destination
See comment in PubMed Commons below
Cancer Res. 2014 May 15;74(10):2825-34. doi: 10.1158/0008-5472.CAN-13-3157. Epub 2014 Mar 19.

EGFR-mediated chromatin condensation protects KRAS-mutant cancer cells against ionizing radiation.

Author information

1
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.
2
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
3
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.

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.

PMID:
24648348
PMCID:
PMC4278592
DOI:
10.1158/0008-5472.CAN-13-3157
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center