Inhibition of the Type III Epidermal Growth Factor Receptor Variant Mutant Receptor by Dominant-Negative EGFR-CD533 Enhances Malignant Glioma Cell Radiosensitivity

Lammering, Guido; Hewit, Theodore H.; Holmes, Mathew; Valerie, Kristoffer; Hawkins, William; Lin, Peck‐Sun; Mikkelsen, Ross B.; Schmidt‐Ullrich, Rupert

doi:10.1158/1078-0432.ccr-04-0393

Cited by 74 publications

(49 citation statements)

References 33 publications

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“…For example, the activating mutation in EGFR has been linked to the radioresistance of malignant gliomas (29,30). The EGFR overexpression has also been linked to the radioresistance of head and neck epidermoid cancer and the inhibition of EGFR improves the radiosensitivity of the cancer (13,31).…”

Section: Discussionmentioning

confidence: 99%

Effect of combining anti-epidermal growth factor receptor antibody C225 and radiation on DU145 prostate cancer

et al. 2008

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Abstract. The epidermal growth factor receptor (EGFR) network has rich targets for prostate cancer killing. Herein we evaluated the effects of combining the EGFR inhibition and radiation on DU145 prostate cancer. We treated DU145 prostate cancer cells with various doses of anti-EGFR antibody (C225) and γ-irradiation (RAD). The effects of the treatment on cell viability and growth were assessed with cell counting, XTT and clonogenic assays. In vivo treatment effects were assessed using a subcutaneous tumor xenograft in mice. Cell cycle distribution and progression were assessed with flow cytometry. The apoptotic components of cell death were quantified using Annexin-V binding assays. The results demonstrated that when combined with radiation, C225 augmented the inhibition of cell viability and growth in the DU145 cell line and EGFR inhibition appeared to have some interaction with RAD. C225 inhibited the growth of implanted DU145 tumors and increased the efficacy of radiation treatment. Flow cytometric analysis suggested that mostly necrotic cell death resulted from the EGFR inhibition or irradiation, although there may be some apoptosis. We drew the conclusion that the inhibition of EGFR augments the radiation killing of DU145 prostate cancer via a combination of cytostatic, necrotic and apoptotic mechanisms.

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Section: Discussionmentioning

confidence: 99%

Effect of combining anti-epidermal growth factor receptor antibody C225 and radiation on DU145 prostate cancer

et al. 2008

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“…The EGFRvIII mutant contains an in-frame deletion of amino acids 6 to 273, resulting in a ligand-independent, constitutively active oncoprotein. EGFRvIII expression has been linked to poor prognosis (23,24) and implicated in modulating radiosensitivity (25). Ionizing radiation in the therapeutic dose range of 1 to 5 Gy increases tyrosine phosphorylation of EGFR wild-type and EGFRvIII, activating mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in Chinese hamster ovary cells (26).…”

Section: Introductionmentioning

confidence: 99%

Epidermal Growth Factor Receptor vIII Expression in U87 Glioblastoma Cells Alters Their Proteasome Composition, Function, and Response to Irradiation

Kim

Brush

Watson

et al. 2008

Molecular Cancer Research

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Little is known about the factors that influence the proteasome structures in cells and their activity, although this could be highly relevant to cancer therapy. We have previously shown that, within minutes, irradiation inhibits substrate degradation by the 26S proteasome in most cell types. Here, we report an exception in U87 glioblastoma cells transduced to express the epidermal growth factor receptor vIII (EGFRvIII) mutant (U87EGFRvIII), which does not respond to irradiation with 26S proteasome inhibition. This was assessed using either a fluorogenic substrate or a reporter gene, the ornithine decarboxylase degron fused to ZsGreen (cODCZsGreen), which targets the protein to the 26S proteasome. To elucidate whether this was due to alterations in proteasome composition, we used quantitative reverse transcription-PCR to quantify the constitutive (X, Y, Z) and inducible 20S subunits (Lmp7, Lmp2, Mecl1), and 11S (PA28A and B) and 19S components (PSMC1 and PSMD4). U87 and U87EGFRvIII significantly differed in expression of proteasome subunits, and in particular immunosubunits. Interestingly, 2 Gy irradiation of U87 increased subunit expression levels by 16% to 324% at 6 hours, with a coincident 30% decrease in levels of the proteasome substrate c-myc, whereas they changed little in U87EGFRvIII. Responses similar to 2 Gy were seen in U87 treated with a proteasome inhibitor, NPI0052, suggesting that proteasome inhibition induced replacement of subunits independent of the means of inhibition. Our data clearly indicate that the composition and function of the 26S proteasome can be changed by expression of the EGFRvIII. How this relates to the increased radioresistance associated with this cell line remains to be established. (Mol Cancer Res 2008;6(3):426 -34)

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“…39 Expression of EGRFvIII has been found to augment proliferation and inhibit apoptosis, [40][41][42] promote tumor cell motility, 43 and confer resistance to radiation and chemotherapy. [44][45][46] Interestingly, clinical and biochemical characteristics associated with poor prognosis in EGFRvIII-negative GBMs do not predict outcome in EGFRvIII-positive GBM. 47 Among GBM patients who have undergone gross total resection of their tumors and survived beyond 1 y of diagnosis, expression of EGFRvIII has been found to be an independent negative prognostic indicator.…”

Section: Egfr As a Potential Targetmentioning

confidence: 99%

The evolution of the EGFRvIII (rindopepimut) immunotherapy for glioblastoma multiforme patients

Paff

Alexandru-Abrams

Hsu

et al. 2014

Human Vaccines & Immunotherapeutics

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Inhibition of the Type III Epidermal Growth Factor Receptor Variant Mutant Receptor by Dominant-Negative EGFR-CD533 Enhances Malignant Glioma Cell Radiosensitivity

Cited by 74 publications

References 33 publications

Effect of combining anti-epidermal growth factor receptor antibody C225 and radiation on DU145 prostate cancer

Effect of combining anti-epidermal growth factor receptor antibody C225 and radiation on DU145 prostate cancer

Epidermal Growth Factor Receptor vIII Expression in U87 Glioblastoma Cells Alters Their Proteasome Composition, Function, and Response to Irradiation

The evolution of the EGFRvIII (rindopepimut) immunotherapy for glioblastoma multiforme patients

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