G2 checkpoint targeting via Wee1 inhibition radiosensitizes EGFRvIII-positive glioblastoma cells

Radiation Oncology

Research

Martin Mynarek¹  Fruzsina Gatzemeier²  Kai Rothkamm²  Malte Kriegs²  Sabrina Christiansen²  Cordula Petersen²  Konstantin Hoffer²  Simon Feyerabend²  Meryem H. Cetin²  Britta Riepen²  Thorsten Rieckmann³  Nina Struve⁴  Melanie Schoof⁵  Ulrich Schüller⁶ 

[1] Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Mildred-Scheel Cancer Career Center HaTriCs4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Department of Radiobiology & Radiation Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany;Department of Radiobiology & Radiation Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany;Department of Otolaryngology and Head and Neck Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Department of Radiobiology & Radiation Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany;Mildred-Scheel Cancer Career Center HaTriCs4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Research Institute Children’s Cancer Center Hamburg, Hamburg, Germany;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Research Institute Children’s Cancer Center Hamburg, Hamburg, Germany;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;

关键词: Glioblastoma;    EGFRvIII;    Wee1 inhibition;    Adavosertib;    X-irradiation;    Radiosensitization;   

DOI  :  10.1186/s13014-023-02210-x

 received in 2022-05-11, accepted in 2023-01-19,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundThe gene of the Epidermal growth factor receptor (EGFR) is one of the most frequently altered genes in glioblastoma (GBM), with deletions of exons 2–7 (EGFRvIII) being amongst the most common genomic mutations. EGFRvIII is heterogeneously expressed in GBM. We already showed that EGFRvIII expression has an impact on chemosensitivity, replication stress, and the DNA damage response. Wee1 kinase is a major regulator of the DNA damage induced G2 checkpoint. It is highly expressed in GBM and its overexpression is associated with poor prognosis. Since Wee1 inhibition can lead to radiosensitization of EGFRvIII-negative (EGFRvIII−) GBM cells, we asked, if Wee1 inhibition is sufficient to radiosensitize also EGFRvIII-positive (EGFRvIII+) GBM cells.MethodsWe used the clinically relevant Wee1 inhibitor adavosertib and two pairs of isogenetic GBM cell lines with and without endogenous EGFRvIII expression exhibiting different TP53 status. Moreover, human GBM samples displaying heterogenous EGFRvIII expression were analyzed. Expression of Wee1 was assessed by Western blot and respectively immunohistochemistry. The impact of Wee1 inhibition in combination with irradiation on cell cycle and cell survival was analyzed by flow cytometry and colony formation assay.ResultsAnalysis of GBM cells and patient samples revealed a higher expression of Wee1 in EGFRvIII+ cells compared to their EGFRvIII− counterparts. Downregulation of EGFRvIII expression by siRNA resulted in a strong decrease in Wee1 expression. Wee1 inhibition efficiently abrogated radiation-induced G2-arrest and caused radiosensitization, without obvious differences between EGFRvIII− and EGFRvIII+ GBM cells.ConclusionWe conclude that the inhibition of Wee1 is an effective targeting approach for the radiosensitization of both EGFRvIII− and EGFRvIII+ GBM cells and may therefore represent a promising new therapeutic option to increase response to radiotherapy.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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