G2 checkpoint targeting via Wee1 inhibition radiosensitizes EGFRvIII-positive glioblastoma cells
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G2 checkpoint targeting via Wee1 inhibition radiosensitizes EGFRvIII-positive glioblastoma cells. / Cetin, Meryem H; Rieckmann, Thorsten; Hoffer, Konstantin; Riepen, Britta; Christiansen, Sabrina; Gatzemeier, Fruzsina; Feyerabend, Simon; Schoof, Melanie; Schüller, Ulrich; Petersen, Cordula; Mynarek, Martin; Rothkamm, Kai; Kriegs, Malte; Struve, Nina.
In: RADIAT ONCOL, Vol. 18, No. 1, 19, 29.01.2023.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - G2 checkpoint targeting via Wee1 inhibition radiosensitizes EGFRvIII-positive glioblastoma cells
AU - Cetin, Meryem H
AU - Rieckmann, Thorsten
AU - Hoffer, Konstantin
AU - Riepen, Britta
AU - Christiansen, Sabrina
AU - Gatzemeier, Fruzsina
AU - Feyerabend, Simon
AU - Schoof, Melanie
AU - Schüller, Ulrich
AU - Petersen, Cordula
AU - Mynarek, Martin
AU - Rothkamm, Kai
AU - Kriegs, Malte
AU - Struve, Nina
N1 - © 2023. The Author(s).
PY - 2023/1/29
Y1 - 2023/1/29
N2 - BACKGROUND: The 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.METHODS: We 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.RESULTS: Analysis 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.CONCLUSION: We 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.
AB - BACKGROUND: The 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.METHODS: We 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.RESULTS: Analysis 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.CONCLUSION: We 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.
KW - Humans
KW - Glioblastoma/drug therapy
KW - ErbB Receptors/genetics
KW - Cell Cycle
KW - Cell Cycle Proteins/genetics
KW - Cell Line, Tumor
KW - Brain Neoplasms/radiotherapy
KW - Protein-Tyrosine Kinases/genetics
U2 - 10.1186/s13014-023-02210-x
DO - 10.1186/s13014-023-02210-x
M3 - SCORING: Journal article
C2 - 36709315
VL - 18
JO - RADIAT ONCOL
JF - RADIAT ONCOL
SN - 1748-717X
IS - 1
M1 - 19
ER -
