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Therapeutics, Targets, and Chemical Biology

EGFR/JIP-4/JNK2 Signaling Attenuates Cetuximab-Mediated Radiosensitization of Squamous Cell Carcinoma Cells

Iris Eke, Lydia Schneider, Claudia Förster, Daniel Zips, Leoni A. Kunz-Schughart and Nils Cordes
Iris Eke
Authors' Affiliations: OncoRay—National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus; and Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
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Lydia Schneider
Authors' Affiliations: OncoRay—National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus; and Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
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Claudia Förster
Authors' Affiliations: OncoRay—National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus; and Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
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Daniel Zips
Authors' Affiliations: OncoRay—National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus; and Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, GermanyAuthors' Affiliations: OncoRay—National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus; and Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
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Leoni A. Kunz-Schughart
Authors' Affiliations: OncoRay—National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus; and Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
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Nils Cordes
Authors' Affiliations: OncoRay—National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus; and Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, GermanyAuthors' Affiliations: OncoRay—National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus; and Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
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DOI: 10.1158/0008-5472.CAN-12-2021 Published January 2013
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Abstract

EGF receptor (EGFR) promotes tumor growth as well as radio- and chemoresistance in various human malignancies including squamous cell carcinomas (SCC). In addition to deactivation of prosurvival signaling, cetuximab-mediated EGFR targeting might concomitantly induce self-attenuating signaling bypasses. Identification of such bypass mechanisms is key to improve the efficacy of targeted approaches. Here, we show great similarity of EGFR signaling and radiation survival in cetuximab-treated SCC cells grown in a more physiologic three-dimensional extracellular matrix and as tumor xenografts in contrast to conventional monolayer cell cultures. Using phosphoproteome arrays, we observed strong induction of JNK2 phosphorylation potentially resulting from cetuximab-inhibited EGFR through c-jun-NH2-kinase (JNK)-interacting protein-4 (JIP-4), which was identified using an immunoprecipitation-mass spectrometric approach. Inhibition of this signaling bypass by JIP-4 or JNK2 knockdown or pharmacologic JNK2 inhibition enhanced cetuximab efficacy and tumor cell radiosensitivity. Our findings add new facets to EGFR signaling and indicate signaling bypass possibilities of cancer cells to improve their survival on cetuximab treatment. By deactivation of cetuximab–self-attenuating JNK2-dependent signaling, the cytotoxicity, and radiosensitizing potential of cetuximab can be augmented. Cancer Res; 73(1); 297–306. ©2012 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received May 29, 2012.
  • Revision received September 12, 2012.
  • Accepted October 3, 2012.
  • ©2012 American Association for Cancer Research.
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Cancer Research: 73 (1)
January 2013
Volume 73, Issue 1
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EGFR/JIP-4/JNK2 Signaling Attenuates Cetuximab-Mediated Radiosensitization of Squamous Cell Carcinoma Cells
Iris Eke, Lydia Schneider, Claudia Förster, Daniel Zips, Leoni A. Kunz-Schughart and Nils Cordes
Cancer Res January 1 2013 (73) (1) 297-306; DOI: 10.1158/0008-5472.CAN-12-2021

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EGFR/JIP-4/JNK2 Signaling Attenuates Cetuximab-Mediated Radiosensitization of Squamous Cell Carcinoma Cells
Iris Eke, Lydia Schneider, Claudia Förster, Daniel Zips, Leoni A. Kunz-Schughart and Nils Cordes
Cancer Res January 1 2013 (73) (1) 297-306; DOI: 10.1158/0008-5472.CAN-12-2021
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