Radiation-induced activation of a common variant of EGFR confers enhanced radioresistance

Lammering, Guido; Valerie, Kristoffer; Lin, Peck‐Sun; Hewit, Theodore H.; Schmidt‐Ullrich, Rupert

doi:10.1016/j.radonc.2004.07.004

Cited by 83 publications

(56 citation statements)

References 24 publications

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“…1A). Modulation of radiosensitivity by the EGFRvIII mutant has been reported in vitro and in vivo (26,32). In in vitro studies, the expression of EGFRvIII by either transfection or adenoviral delivery enhanced radioresistance in Chinese hamster ovary and U373 cell lines, respectively.…”

Section: Discussionmentioning

confidence: 98%

“…Follow-up experiments to determine the phosphorylation status and the targeted proteasome subunits of EGFR pathway using proteomics tools and/or small-molecule inhibitors of this pathway would be helpful to understand the mechanism of the radiation resistance conferred by EGFRvIII. It is worth noting that radiation leads to rapid phosphorylation of EGFR and EGFRvIII, and to activation of downstream pathways (32,40) that might lead to changes in proteasome phosphorylation status and activity.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

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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“…Modulation of radiosensitivity by the EGFRvIII mutant has been reported in vitro and in vivo (26,33). In in vitro studies, the expression of EGFRvIII by either transfection or adenoviral delivery enhanced radioresistancy in CHO and U373 cell lines, respectively.…”

Section: Discussionmentioning

confidence: 98%

“…HLA-A2.1 mice were injected with DCs treated with or without 10 Gy and pulsed with PSA-3 peptide. Spleens were harvested 10-14 days after DC immunization and restimulated with either PSA-3 or non-specific peptide MART-1 (27)(28)(29)(30)(31)(32)(33)(34)(35) or no stimulation. The production of IFN-gamma and IL-4 were assessed by ELISPOT.…”

Section: Key Research Accomplishmentsmentioning

confidence: 99%

Radiation Effects on the Immune Response to Prostate Cancer

McBride¹

2009

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE 01-02-2008 REPORT TYPE Annual DATES COVERED PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERUniversity of California Los Angeles, CA 90024 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTRadiation therapy (RT) is the front line treatment for prostate cancer in the early stages but is relatively ineffective against large tumor volumes and it is difficult to use it against micrometastatic disease. Immunotherapy (IT) has become popular as an alternative treatment since the discovery of prostate tumor-associated antigens (TAA) and of corresponding tumor-specific T cells in prostate cancer patients. However, IT is not a very effective modality on its own due to multiple tumor escape mechanisms and probably would benefit from combination with other therapies, such as RT. At least in theory, a potential advantage is that radiation affects the immune system by upregulating MHC class I and co-stimulatory molecules, which could promote T cell filtration into tumors and T cell activation. On the other hand, we recently showed that radiation affects proteasome function, which could affect antigen processing, and appears to have other effects on DC antigen presentation. In the first year of this study, we have been constructing cell lines to examine this in prostate cancer. We have also examined the effects of radiation on DC processing PSA either endogenously or exogenously as well as on proteasome and immunoproteasome function in DCs. The final goal of the proposal is to determine if radiation affects the hierarchy of antigenic peptide presented by DCs and tumor cells and to devise better strategies in combination treatments of RT and IT. SUBJECT TERMS IntroductionRadiation therapy (RT) is a very effective treatment for early stage cancer but not for large tumors or for distant micrometastatic disease. R...

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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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Radiation-induced activation of a common variant of EGFR confers enhanced radioresistance

Cited by 83 publications

References 24 publications

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

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

Radiation Effects on the Immune Response to Prostate Cancer

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

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