The epidermal growth factor receptor mediates radioresistance

Liang, Ke; Ang, K. Kian; Milas, Luka; Hunter, Nancy; Fan, Zhen

doi:10.1016/s0360-3016(03)00511-x

Cited by 263 publications

(165 citation statements)

References 28 publications

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“…These observations suggest that effects of nimotuzumab on both NSCLC cell proliferation and tumour angiogenesis might contribute to the enhancement of the antitumor efficacy of radiation by this antibody observed in the present study. Enhancement of the anticancer effect of radiation by the anti-EGFR mAb cetuximab was previously shown to be increased by transfection of cells to upregulate the level of EGFR expression, suggesting that potentiation of the antitumor efficacy of radiation by anti-EGFR mAbs is related to the absolute level of EGFR expression (Liang et al, 2003;Bonner et al, 2004). This finding is consistent with our present results showing that potentiation of the antitumor activity of radiation by nimotuzumab was related to the level of surface EGFR expression.…”

Section: Discussionsupporting

confidence: 93%

Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status

et al. 2008

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The expression and activity of the epidermal growth factor receptor (EGFR) are determinants of radiosensitivity in several tumour types, including non-small cell lung cancer (NSCLC). However, little is known of whether genetic alterations of EGFR in NSCLC cells affect the therapeutic response to monoclonal antibodies (mAbs) to EGFR in combination with radiation. We examined the effects of nimotuzumab, a humanised mAb to EGFR, in combination with ionising radiation on human NSCLC cell lines of differing EGFR status. Flow cytometry revealed that H292 and Ma-1 cells expressed high and moderate levels of EGFR on the cell surface, respectively, whereas H460, H1299, and H1975 cells showed a low level of surface EGFR expression. Immunoblot analysis revealed that EGFR phosphorylation was inhibited by nimotuzumab in H292 and Ma-1 cells but not in H460, H1299, or H1975 cells. Nimotuzumab augmented the cytotoxic effect of radiation in H292 and Ma-1 cells in a clonogenic assay in vitro, with a dose enhancement factor of 1.5 and 1.3, respectively. It also enhanced the antitumor effect of radiation on H292 and Ma-1 cell xenografts in nude mice, with an enhancement factor of 1.3 and 4.0, respectively. Nimotuzumab did not affect the radioresponse of H460 cells in vitro or in vivo. Nimotuzumab enhanced the antitumor efficacy of radiation in certain human NSCLC cell lines in vitro and in vivo. This effect may be related to the level of EGFR expression on the cell surface rather than to EGFR mutation.

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Section: Discussionsupporting

confidence: 93%

Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status

et al. 2008

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“…It has been shown by numerous studies that the activation of the PI3K/Akt signaling pathway in tumor cells, either by increased growth factor receptor signaling (20,21) or decreased activity of specific pathway inhibitors such as Figure 4. The interaction of caffeine with p53/p21 Waf1 and p-Akt Ser437 expression levels.…”

Section: Discussionmentioning

confidence: 99%

Caffeine Confers Radiosensitization of PTEN-Deficient Malignant Glioma Cells by Enhancing Ionizing Radiation–Induced G1 Arrest and Negatively Regulating Akt Phosphorylation

Sinn

Tallen²,

Schroeder³

et al. 2010

Molecular Cancer Therapeutics

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PTEN mutations are frequently found in malignant glioma and can result in activated phosphatidylinositol-3-kinase/Akt survival signaling associated with resistance to radiotherapy. Strategies to interfere with aberrant PI3K/Akt activity are therefore being developed to improve the therapeutic efficacy of radiotherapy in patients with malignant glioma. The methylxanthine caffeine has been described as a PI3K inhibitor and is also known to sensitize cells to ionizing radiation. However, a direct association between these two caffeinemediated effects has not been reported yet. Therefore, we asked whether caffeine or its derivative pentoxifylline differentially affect the radiosensitivity of malignant gliomas with different PTEN status. As models, we used the radiosensitive EA14 malignant glioma cell line containing wild-type PTEN and the radioresistant U87MG malignant glioma cell line harboring mutant PTEN. Our study revealed that caffeine and pentoxifylline radiosensitized PTEN-deficient but not PTEN-proficient glioma cells. Radiosensitization of PTENdeficient U87MG cells by caffeine was significantly correlated with the activation of the G 1 DNA damage checkpoint that occurred independently of de novo synthesis of p53 and p21. The p53 independency was also confirmed by a significant caffeine-mediated radiosensitization of the glioma cell lines T98G and U373MG that are deficient for both PTEN and p53. Furthermore, caffeine-mediated radiosensitization was associated with the inhibition of Akt hyperphosphorylation in PTEN-deficient cells to a level comparable with PTEN-proficient cells. Our data suggest that the methylxanthine caffeine or its derivative pentoxifylline are promising candidate drugs for the radiosensitization of glioma cells particularly with PTEN mutations. Mol Cancer Ther; 9(2); 480-8. ©2010 AACR.

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“…This mechanism may also play a role in radioresistance of RAS-mutated tumors. Moreover, experimental and clinical evidence exists that overexpression or mutation of EGFR mediates tumor resistance to both chemotherapy and especially radiotherapy (18)(19)(20)(21)(22)(23), and EGFR overexpression has been correlated with accelerated repopulation of tumors undergoing radiotherapy (24).…”

Section: Introductionmentioning

confidence: 99%

Stimulated PI3K-AKT Signaling Mediated through Ligand or Radiation-Induced EGFR Depends Indirectly, but not Directly, on Constitutive K-Ras Activity

Toulany

Baumann

Rodemann

2007

Molecular Cancer Research

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The epidermal growth factor receptor mediates radioresistance

Cited by 263 publications

References 28 publications

Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status

Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status

Caffeine Confers Radiosensitization of PTEN-Deficient Malignant Glioma Cells by Enhancing Ionizing Radiation–Induced G1 Arrest and Negatively Regulating Akt Phosphorylation

Stimulated PI3K-AKT Signaling Mediated through Ligand or Radiation-Induced EGFR Depends Indirectly, but not Directly, on Constitutive K-Ras Activity

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