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Nuclear EGFR as Novel Therapeutic Target

Insights into Nuclear Translocation and Function

Der nukleäre EGFR als neues therapeutisches Ziel. Einsichten in die nukleäre Translokation und Funktion

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An Erratum to this article was published on 28 January 2010

Emerging evidence suggests the existence of a new mode of epidermal growth factor receptor (EGFR) signaling in which activated EGFR undergoes nuclear translocation following treatment with ionizing radiation. The authors provide evidence that the nuclear EGFR transport is a stress-specific cellular reaction, which is linked to src-dependent EGFR internalization into caveolae. These flask-shaped pits can fuse with endoplasmic reticulum and the EGFR is sorted into a perinuclear localization. This compartment may serve as a reservoir for nuclear EGFR transport which is regulated by PKCε (protein kinase Cepsilon). Nuclear EGFR is able to induce transcription of genes essential for cell proliferation and cell-cycle regulation. Moreover, nuclear EGFR has physical contact with compounds of the DNA repair machinery and is involved in removal of DNA damage. Anti-EGFR strategies target radiation-associated EGFR nuclear translocation in different manners. EGFR-inhibitory antibodies, i.e., cetuximab (Erbitux®), can block nuclear translocation by EGFR immobilization within the cytosol in responder cell lines, whereas tyrosine kinase inhibitors rather target nuclear kinase activity of EGFR linked with cytosolic or nuclear functions. However, both strategies can inhibit DNA repair following irradiation.

Der EGFR wird als membranständiger Wachstumsfaktor-Rezeptor beschrieben. Neue Erkenntnisse zeigten jedoch, dass der EGFR z. B. nach Bestrahlung auch im Zellkern gefunden werden kann. Der Kerntransport des EGFR wird vor allem nach Stressexposition der Zelle beobachtet und ist mit einer Src-Kinase-abhängigen Internalisierung des EGFR in das endosomale Kompartment der Caveolae assoziiert. Nach Verschmelzung der Caveolae mit der Membran des endoplasmatischen Retikulums reichert sich der EGFR perinukleär an. Der perinukleäre EGFR-Pool dient wahrscheinlich als Reservoir für den Kerntransport, der nach Strahlenexposition durch die Aktivität der PKCε (Proteinkinase Cepsilon) reguliert wird. Der nukleäre EGFR agiert zum einen als Transkriptionsfaktor und induziert die Transkription von zellzyklus- und proliferationsrelevanten Proteinen, zum anderen hat er physikalischen Kontakt zu für die DNA-Reparatur essentiellen Proteinen. In der Radioonkologie finden prinzipiell zwei Anti-EGFR-Therapien Verwendung. Antikörperstrategien, z. B. die Behandlung mit Cetuximab (Erbitux®), können in sensitiven Tumorzellen zu einer Immobilisierung des internalisierten EGFR in den Caveolae führen. Die Translokation in den Zellkern ist blockiert. Im Gegensatz dazu verhindern Kinaseinhibitoren die strahleninduzierte Kerntranslokation des EGFR nicht, hemmen aber die EGFR-Kinaseaktivität und blockieren so das nukleäre und zytoplasmatische "Signaling" des Rezeptors. Auf diese Weise können beide Strategien die Reparatur von DNA-Schäden behindern und den Erfolg einer radioonkologischen Behandlung verbessern.

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  1. Division of Radiobiology and Molecular Environmental Research, Department of Radiooncology, University of Tübingen, Tübingen, Germany

    Klaus Dittmann, Claus Mayer & H. Peter Rodemann

  2. Division of Radiobiology and Molecular Environmental Research, Department of Radiooncology, Eberhard Karls University, Röntgenweg 11, 72076, Tübingen, Germany

    Klaus Dittmann

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  1. Klaus Dittmann
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Correspondence to Klaus Dittmann.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00066-010-7001-6

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Dittmann, K., Mayer, C. & Rodemann, H.P. Nuclear EGFR as Novel Therapeutic Target. Strahlenther Onkol 186, 1–6 (2010). https://doi.org/10.1007/s00066-009-2026-4

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