Simultaneous Inhibition of Epidermal Growth Factor Receptor (EGFR) Signaling and Enhanced Activation of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Receptor-mediated Apoptosis Induction by an scFv:sTRAIL Fusion Protein with Specificity for Human EGFR

Bremer, Edwin; Samplonius, Douwe F.; Genne, Linda van; Dijkstra, Marike H.; Kroesen, Bart-Jan; Leij, Lou F. M. H. de; Helfrich, Wijnand

doi:10.1074/jbc.m413673200

Cited by 91 publications

(70 citation statements)

References 51 publications

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“…22,23 We already reported that ad-TRAIL could overcome TRAIL resistance in several TRAIL-resistant cell lines. 14 Recently, tumor-cell selective modification of soluble TRAIL by fusing epidermal growth factor receptordirected antibody (scFv425) showed a more selective and potent antitumor effect, 24 and a recombinant adenovirus that can express fusion protein (scFv425-TRAIL) demonstrated its clinical significance. 25 However, resistance to TRAIL prevents its clinical use and requires the combination with other chemicals.…”

Section: Discussionmentioning

confidence: 99%

Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells

Park

et al. 2011

Cancer Gene Ther

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Soluble TRAIL and adenovirus (ad)-TRAIL exhibit a strong antitumor effect by inducing apoptosis. Vorinostat is the histone deacetylase (HDAC) inhibitor that induces cell death in cancer cell lines and regulates the expression of epigenetically silenced genes, such as Coxackie adenoviral receptor (CAR), the receptor for adenoviral entry. We propose a new strategy in which vorinostat will induce high expression of ad-TRAIL and a strong antitumor response, and investigated the mechanism involved. The effect of vorinostat on transcription and expression of TRAIL from ad-TRAIL-transduced lung cancer cells were confirmed by reverse transciption-PCR (RT-PCR), quantitative real time-PCR and western blot assay. Anti-tumor effects were measured after cotreatment of vorinostat and ad-TRAIL, and the drug interactions were analyzed. After combined treatment of vorinostat and ad-TRAIL, apoptosis and western blot assays for Akt, Bcl-2 and caspase were performed. Vorinostat increased the expression of CAR in lung cancer cell lines and increased the expression of luciferase (luc) from ad-luc-transduced cells and TRAIL from ad-TRAIL-transduced cells. RT-PCR and quantitative real time-PCR, after sequential vorinostat treatment, revealed that vorinostat may enhance TRAIL expression from ad-TRAIL by increasing transduction through enhanced CAR expression and increasing adenoviral transgene transcription. Combined vorinostat and ad-TRAIL treatment showed the synergistic anti-tumor effect in lung cancer cell lines. Combined vorinostat and ad-TRAIL induced stronger apoptosis induction, suppression of NF-kB activation and breakdown of the anti-apoptotic molecule Bcl-2. In conclusion, the vorinostat synergistically enhanced the anti-tumor effect of ad-TRAIL by (1) increasing adenoviral transduction through the increased expression of CAR and (2) increasing adenoviral transgene (TRAIL) transcription in lung cancer cell lines.

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Section: Discussionmentioning

confidence: 99%

Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells

Park

et al. 2011

Cancer Gene Ther

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“…In contrast, other anti-EGFR scFv-TRAIL fusion proteins showed rapid inactivation of the EGFR signaling pathways in various other tumor cell lines (e.g., A431; ref. 26). In our study, we applied a humanized version of clinically approved antibody cetuximab for the generation of the antibody-scTRAIL fusion proteins.…”

Section: Discussionmentioning

confidence: 99%

Tetravalent Antibody–scTRAIL Fusion Proteins with Improved Properties

Seifert

Plappert

Fellermeier

et al. 2014

Molecular Cancer Therapeutics

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We applied the immunoglobulin E (IgE) heavy-chain domain 2 (EHD2) as the covalently linked homodimerization module to generate antibody-scTRAIL fusion proteins. By fusing a humanized single-chain fragment variable (scFv) directed against EGFR to the N-terminus of the EHD2 and a single-chain derivative of TRAIL (scTRAIL) to the C-terminus of the EHD2, we produced a dimeric, tetravalent fusion protein. The fusion protein retained its binding activity for EGFR and TRAIL receptors. In vitro, the targeted antibody-scTRAIL fusion protein exhibited an approximately 8-to 18-fold increased cytotoxic activity compared with the untargeted EHD2-scTRAIL fusion protein. This resulted in increased antitumor activity in a subcutaneous Colo205 xenograft tumor murine model. In summary, the scFv-EHD2-scTRAIL fusion protein combines target cell selectivity with an increased TRAIL activity leading to improved antitumor activities.

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“…Positive controls included a glioblastoma tumour sample expressing both the wild-type EGFR (wtEGFR) and EGFRvIII, and a cell line transfected with an EGFRvIII plasmid (Jurkat.EGFRvIII; Bremer et al, 2005).…”

Section: Rt -Pcr For Egfrviiimentioning

confidence: 99%

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

et al. 2008

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Ovarian cancer is the most frequent cause of death from gynaecological cancer in the Western world. Current prognostic factors do not allow reliable prediction of response to chemotherapy and survival for individual ovarian cancer patients. Epidermal growth factor receptor (EGFR) and HER-2/neu are frequently expressed in ovarian cancer but their prognostic value remains unclear. In this study, we investigated the expression and prognostic value of EGFR, EGFR variant III (EGFRvIII), HER-2/neu and important downstream signalling components in a large series of epithelial ovarian cancer patients. Immunohistochemical staining of EGFR, pEGFR, EGFRvIII, Her-2/neu, PTEN (phosphatase and tensin homologue deleted on chromosome 10), total and phosphorylated AKT (pAKT) and phosphorylated ERK (pERK) was performed in 232 primary tumours using the tissue microarray platform and related to clinicopathological characteristics and survival. In addition, EGFRvIII expression was determined in 45 tumours by RT -PCR. Our results show that negative PTEN immunostaining was associated with stage I/II disease (P ¼ 0.006), non-serous tumour type (P ¼ 0.042) and in multivariate analysis with a longer progression-free survival (P ¼ 0.015). Negative PTEN staining also predicted improved progression-free survival in patients with grade III or undifferentiated serous carcinomas (P ¼ 0.011). Positive pAKT staining was associated with advanced-stage disease (P ¼ 0.006). Other proteins were expressed only at low levels, and were not associated with any clinicopathological parameter or survival. None of the tumours were positive for EGFRvIII. In conclusion, our results indicate that tumours showing negative PTEN staining could represent a subgroup of ovarian carcinomas with a relatively favourable prognosis.

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Simultaneous Inhibition of Epidermal Growth Factor Receptor (EGFR) Signaling and Enhanced Activation of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Receptor-mediated Apoptosis Induction by an scFv:sTRAIL Fusion Protein with Specificity for Human EGFR

Abstract: Epidermal growth factor receptor (EGFR) signaling inhibition by monoclonal antibodies and EGFR-specific

Cited by 91 publications

References 51 publications

Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells

Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells

Tetravalent Antibody–scTRAIL Fusion Proteins with Improved Properties

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

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