EGFR and erbB2 in malignant peripheral nerve sheath tumors and implications for targeted therapy

¹ Institute of Neuropathology, Charité-Universitätsmedizin Berlin, Germany
² Institute of Pathology, Helios-Klinikum Emil von Behring, Berlin, Germany
³ Department of Neuropathology, Ruprecht-Karls-University Heidelberg, and Deutsches Krebsforschungszentrum Heidelberg, Germany
⁴ Department of Neuropathology, Friedrich-Schiller-University Jena, Germany
⁵ Department of Maxillofacial Surgery, University Hospital Eppendorf, Hamburg, Germany
⁶ Institute of Pathology, University Hospital Bonn, Germany

^* To whom correspondence should be addressed. E-mail: nikola.holtkamp{at}charite.de.

	Abstract

Malignant peripheral nerve sheath tumors MPNST are sarcomas with poor prognosis and limited treatment options. Evidence for a role of EGFR and erbB2 in MPNST led us to systematically study these potential therapeutic targets in a larger tumor panel n=37. Multiplex ligation-dependent probe amplification MLPA and FISH analysis revealed increased EGFR dosage in 28% of MPNST. ERBB2 and 3 tumor suppressor genes PTEN, CDKN2A, TP53 were frequently lost or reduced. Reduction of CDKN2A was linked to appearance of metastasis. Comparison of corresponding neurofibromas and MPNST revealed an increase in genetic lesions in MPNST. No somatic mutations were found within tyrosine kinase encoding exons of EGFR and ERBB2. However, on the protein level expression of EGFR and erbB2 was frequently detected in MPNST. EGFR expression was significantly associated with increased EGFR gene dosage. EGFR ligands TGFA and EGF were more strongly expressed in MPNST than in neurofibromas. The effect of the drugs erlotinib and trastuzumab, which target EGFR and erbB2, was determined on MPNST cell lines. In contrast to trastuzumab, erlotinib mediated dose-dependent inhibition of cell proliferation. EGF-induced EGFR phosphorylation was attenuated by erlotinib. Summarized, our data indicate that EGFR and erbB2 are potential targets in treatment of MPNST patients.

Key Words: MPNST, EGFR, ERBB2, targeted therapy, tumor suppressor gene

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