Science et thérapie du cancer

Cytotoxicity and Radiosensitization of High Grade Glioma Cells by CI-1033, an Irreversible Pan-Erbb Inhibitor

Abstract

Dannis G van Vuurden, Shruti Shukla, Laurine E Wedekind, Gitta K. Kuipers, David P Noske, W Peter Vandertop, M Vincent M Lafleur, Ben J Slotman, Esther Hulleman, Gertjan JL Kaspers and Jacqueline Cloos

Background: High-grade gliomas (HGG) are highly infiltrative malignancies, causing considerable mortality in child- and adulthood, necessitating new therapies. Novel therapies directed against multiple epidermal growth factor family (ErbB) members are potentially effective in HGG.

Aim: To assess ErbB family expression in normal brain and pediatric and adult HGG in silico and to determine radiosensitizing property of the pan-ErbB inhibitor CI-1033, in HGG cells in vitro.

Material and methods: In silico mRNA array expression analysis was performed to assess EGFR, ERBB2, ERBB3, ERBB4 gene expression in normal brain, adult and pediatric HGG. ErbB family protein expression was determined in HGG cell lines using Western blot. Sulforhodamine-B assay was used to assess cytotoxicity of CI- 1033 andclonogenic assays to determine radiosensitization. The effect on cell cycle distribution and PI3K-Akt/Ras- MAPK signalling of CI-1033 ± radiation was measured using flow cytometry.

Results: EGFR and ERBB2 were significantly overexpressed in datasets of pediatric and adult HGG. Heterogeneous protein expression of EGFR, ErbB2, 3 and 4 was observed in HGG cell lines. CI-1033 IC50 values of 1.0 μM, 2.5 μM and 4.3 μMwere found in D384MG, U-251 MG and Gli-6 cells, respectively. CI-1033 significantly sensitized Gli-6 and D384MGcells to radiation, with 24 and 48 hrs pre-treatment respectively.

Conclusion: EGFR and ErbB2 are overexpressed in adult and childhood HGG. Irreversible pan-ErbB inhibition by CI-1033 is cytotoxic and radiosensitizes HGG cell lines in vitro, warranting further in vivo studies.