gms | German Medical Science

67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS)

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

12. - 15. Juni 2016, Frankfurt am Main

Pharmacological WNT-inhibition acts synergistically with chemo- and radiotherapy by overcoming treatment-resistance in glioma stem cells

Meeting Abstract

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  • Abigail K. Suwala - Neurochirurgische Klinik, Universiätsklinikum Düsseldorf, Düsseldorf, Germany
  • Katharina Koch - Neurochirurgische Klinik, Universiätsklinikum Düsseldorf, Düsseldorf, Germany
  • Ulf D. Kahlert - Neurochirurgische Klinik, Universiätsklinikum Düsseldorf, Düsseldorf, Germany
  • Jaroslaw Maciaczyk - Neurochirurgische Klinik, Universiätsklinikum Düsseldorf, Düsseldorf, Germany

Deutsche Gesellschaft für Neurochirurgie. 67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 1. Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS). Frankfurt am Main, 12.-15.06.2016. Düsseldorf: German Medical Science GMS Publishing House; 2016. DocMI.02.04

doi: 10.3205/16dgnc238, urn:nbn:de:0183-16dgnc2386

Veröffentlicht: 8. Juni 2016

© 2016 Suwala et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Objective: Glioma Stem Cells (GSCs) are considered to be responsible for dismal prognosis of Glioblastoma (GBM). WNT signaling is one of the major players in GSCs that promotes their radio- and chemoresistance. In this study we tested whether LGK974, an inhibitor of both canonical and non-canonical WNT signaling, might sensitize GBM cells to chemotherapeutics and irradiation revealing possible mechanisms causing treatment-resistance in GBM.

Method: At first we analyzed MGMT promoter methylation status of several GBM cell lines in order to define cells resistant to the standard chemotherapeutic drug Temozolomide (TMZ). For further investigations we chose two cell lines resistant or sensitive to TMZ, respectively. IC50 concentrations of TMZ and LGK974 as well as IC50 dose of gamma-irradiation were tested via Titer Blue cell viability assay. A drug-response-curve of different concentration of each single therapy and its combination with LGK974 was determined using a computerized simulation of synergism and antagonism in drug combination studies as published previously (Chou, 2006). A reporter assay for canonical WNT/beta-catenin signaling was used to quantify the effect of TMZ and irradiation alone and in combination with LGK974 on the canonical and non-canonical WNT pathway. Western Blot and qPCR were applied to analyze the effects of combinatory therapy on protein and gene expression concerning WNT pathway activation.

Results: We observed a significant synergy of combined irradiation/TMZ with LGK974 in all cell lines. There was no difference in response to combined therapy between cell lines resistant or sensitive to TMZ. Interestingly, following TMZ treatment or irradiation cells showed slightly decreased canonical WNT pathway activity. Furthermore, non-canonical target genes and receptors were upregulated under TMZ chemo- and radiotherapy, suggesting a reciprocal activation of the non-canonical branch of WNT signaling pathway. This phenomenon might possibly be responsible for the development of resistance against standard chemo- and radiotherapy.

Conclusions: We propose that GSCs undergo a shift from canonical to non-canonical WNT signaling to become treatment-resistant under standard chemo- and radiotherapy. Treatment with LGK974 results in therapeutic synergy due to suppression of the therapy-induced non-canonical WNT signaling activation. Our results confirm the potential benefit of combining TMZ or irradiation with the novel WNT inhibitor LGK974 to overcome therapy-resistance in GBM.