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73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

29.05. - 01.06.2022, Köln

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Regulation of the receptor tyrosine kinase AXL in response to therapy and its role in therapy resistance in glioblastoma

Regulation der Rezeptor Tyrosin Kinase AXL als Antwort auf Therapie und die Rolle von AXL in Therapie-Resistenz beim Glioblastom

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  • presenting/speaker Anna-Gila Karbe - Charité – Universitätsmedizin Berlin, Klinik für Neurochirurgie, Berlin, Deutschland
  • Lea Scherschinski - Charité – Universitätsmedizin Berlin, Klinik für Neurochirurgie, Berlin, Deutschland
  • Markus Prem - Charité – Universitätsmedizin Berlin, Klinik für Neurochirurgie, Berlin, Deutschland; Carl Gustav Carus Universitätsklinikum, TU Dresden, Klinik und Poliklinik für Neurochirurgie, Dresden, Deutschland
  • Irina Kremenetskaia - Charité – Universitätsmedizin Berlin, Klinik für Neurochirurgie, Berlin, Deutschland
  • Ingeborg Tinhofer - Charité – Universitätsmedizin Berlin, Klinik für Neurochirurgie, Berlin, Deutschland; German Cancer Consortium (DKTK), Heidelberg, Deutschland
  • Peter Vajkoczy - Charité – Universitätsmedizin Berlin, Klinik für Neurochirurgie, Berlin, Deutschland
  • Julia Sophie Onken - Charité – Universitätsmedizin Berlin, Klinik für Neurochirurgie, Berlin, Deutschland; German Cancer Consortium (DKTK), Heidelberg, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie. Köln, 29.05.-01.06.2022. Düsseldorf: German Medical Science GMS Publishing House; 2022. DocV285

doi: 10.3205/22dgnc276, urn:nbn:de:0183-22dgnc2768

Published: May 25, 2022

© 2022 Karbe et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

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Objective: The receptor tyrosine kinase AXL (RTK-AXL) is implicated in therapy resistance and tumor progression in glioblastoma multiforme (GBM) and might be a useful target in GBM-therapy. Here, we investigate therapy-induced receptor modifications and how endogenous RTK-AXL expression and RTK-AXL inhibition contribute to therapy resistance in GBM.

Methods: We set up in vitro studies with the GBM cell lines U118MG and SF126, which were exposed to increasing doses of temozolomide (TMZ) and radiation (RTX). Receptor modifications as well as down stream signaling in response to both treatment modalities were investigated on protein and mRNA level. Further, we developed TMZ-resistant (TR) cells via continuous exposition of SF126 and U118MG cells to low dose TMZ; TMZ-resistance was confirmed in a colony formation assay. TMZ-resistant and RTK-AXL overexpressing cell lines were exposed to increasing doses of TMZ and RTX, with and without RTK-AXL tyrosine kinase inhibitor (TKI). MTT assay and colony formation assay (CFA) were used to assess cell viability.

Results: The RTK-AXL shedding product, C-terminal AXL (CT-AXL), rises in response to repeated TMZ doses and under hypoxia, a surrogate marker for radio-resistance, whereas AXL-mRNA remains unchanged under both treatment modalities. Endogenous RTX-AXL overexpression leads to therapy resistance, whereas combination therapy of TMZ and RTX with TKI R428 significantly increases therapeutic effects, even in TR-cell lines.

Conclusion: RTK-AXL undergoes post-translational degradation in response to TMZ treatment, and elevated RTK-AXL levels are associated with a decreased therapy response. However, therapy resistance may be overcome by combining TKI to standard treatment. This data provides a rationale for future studies investigating TKI in GBM.