Epidermal growth factor receptor double targeting by a tyrosine kinase inhibitor (Iressa) and a monoclonal antibody (Cetuximab). Impact on cell growth and molecular factors

Fischel, Jean‐Louis; Formento, Patricia; Milano, Gérard

doi:10.1038/sj.bjc.6602428

Cited by 45 publications

(29 citation statements)

References 29 publications

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“…gefitinib, erlotinib) enhanced tumour growth inhibition over that observed with either agent alone (Huang et al, 2004;Matar et al, 2004). However, others have found that combination of cetuximab and gefitinib was antagonistic in all cell lines considered, suggesting that a double-hit strategy with Mabs and TKIs must be considered with caution (Fischel et al, 2005). Another strategy may be combination of EGFR antagonists (Mab or TKI) with inhibitors of RAS or phosphatidyl inositol-3 kinase pathways, which are downstream of the EGFR (e.g.…”

Section: Rash and Clinical Outcomementioning

confidence: 99%

Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck

2007

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Despite significant advances in the use of surgery, chemotherapy and radiotherapy to treat squamous cell carcinoma of the head and neck (SCCHN), prognosis has improved little over the past 30 years. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of SCCHN disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. The epidermal growth factor receptor (EGFR) is expressed at much higher levels in SCCHN tumours than in normal epithelial tissue, and EGFR expression correlates with poor prognosis. Therefore, much effort is currently directed toward targeting aberrant EGFR activity (e.g. cell signalling) in SCCHN. This review discusses the efficacy of novel therapies targeting the EGFR (e.g. anti-EGFR antibodies and EGFR tyrosine kinase inhibitors) that are currently tested in SCCHN patients.

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Section: Rash and Clinical Outcomementioning

confidence: 99%

Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck

2007

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“…Indeed, in two recent studies, cotargeting of the EGFR with a combination of cetuximab and gefitinib or erlotinib was shown to be superior over the targeting of tumor cells with the single agent (25,26). More recently, the combination of cetuximab with gefitinib was reported to induce an antagonistic effect in EGFR-positive tumor cells (27).…”

Section: Introductionmentioning

confidence: 99%

Responses of Human Colorectal Tumor Cells to Treatment with the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody ICR62 Used Alone and in Combination with the EGFR Tyrosine Kinase Inhibitor Gefitinib

Cunningham

Thomas

Fan³

et al. 2006

Cancer Research

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The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab has been approved for the treatment of patients with metastatic colorectal cancer. However, there is currently no reliable marker for response to therapy with the EGFR inhibitors. In this study, we investigated the sensitivity of 10 human colorectal tumor cell lines (DiFi, CCL218, CCL221, CCL225, CCL227, CCL228, CCL231, CCL235, CCL244, and HCT-116) to treatment with our anti-EGFR monoclonal antibody, ICR62, and/or the EGFR tyrosine kinase inhibitor, gefitinib. Of the cells examined, only DiFi contained high levels of constitutively active EGFR and were highly sensitive to treatment with both ICR62 (IC 50 = 0.52 nmol/L) and gefitinib (IC 50 = 27.5 nmol/L). In contrast, the growth of other tumor cell lines, which contained low levels of the EGFR, HER-2, and pAkt but comparable or even higher basal levels of phosphorylated mitogen-activated protein kinase (pMAPK), were relatively resistant to treatment with both inhibitors. Both ICR62 and gefitinib induced EGFR down-regulation, reduced the basal levels of pEGFR at five known tyrosine residues, pMAPK, and pAkt, and increased the sub-G 1 population in DiFi cells. However, treatment with a combination of ICR62 and gefitinib neither sensitized colorectal tumor cells that were insensitive to treatment with the single agent nor enhanced the growthinhibitory effect of the single agent in DiFi cells. These results indicate that basal levels of pMAPK and pAkt are not good indicators of response to the EGFR inhibitors in colorectal cancer cells and dual targeting of the EGFR by a combination of ICR62 and gefitinib is not superior to treatment with a single agent. (Cancer Res 2006; 66(15): 7708-15)

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“…The combined administration of exemestane and erlotinib reduced cell numbers in all cell lines examined in this study. However, inhibitor synergy was identified only in H23 cells according to a formula that Fischel et al (2005) previously described (Figure 1c, d, e).…”

Section: Resultsmentioning

confidence: 99%

The combination of antitumor drugs, exemestane and erlotinib, induced resistance mechanism in H358 and A549 non-small cell lung cancer (NSCLC) cell lines

Kritikou

Giannopoulou

Koutras

et al. 2013

Pharmaceutical Biology

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Context: Estrogens in non-small-cell lung cancer (NSCLC) are important, and their interaction with epidermal growth factor receptor (EGFR) might be crucial. Objective: This study investigates the effect of exemestane, an aromatase inhibitor, and erlotinib, an EGFR inhibitor, on human NSCLC cell lines; H23, H358 and A549. Materials and methods: A cell proliferation assay was used for measuring cell number, apoptosis assay for detecting apoptosis and necrosis and immunoblotting for beclin-1 and Bcl-2 proteins detection. An immunofluorescence assay was used for EGFR localization. A migration assay and zymography were used for cell motility and metalloproteinases (MMPs) expression, respectively. Results: Exemestane, erlotinib or their combination decreased cell proliferation and increased apoptosis. Exemestane's half maximal inhibitory concentration (IC 50 ) was 50 mM for H23 and H358 cells and 20 mM for A549. The IC 50 of erlotinib was 25 mM for all cell lines. Apoptosis increase induced by exemestane was 58.0 (H23), 186.3 (H358) and 34.7% (A549) and by erlotinib was 16.7 (H23), 65.3 (H358) and 66.3% (A549). A synergy effect was observed only in H23 cells. Noteworthy, the combination of exemestane and erlotinib decreased beclin-1 protein levels (32.3 AE 19.2%), an indicator of autophagy, in H23 cells. The combination of exemestane and erlotinib partially reversed the EGFR translocation to mitochondria and decreased MMP levels and migration. Discussion and conclusions: The benefit from a dual targeting of aromatase and EGFR seems to be regulated by NSCLC cell content. The diverse responses of cells to agents might be influenced by the dominance of certain molecular pathways.

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Epidermal growth factor receptor double targeting by a tyrosine kinase inhibitor (Iressa) and a monoclonal antibody (Cetuximab). Impact on cell growth and molecular factors

Cited by 45 publications

References 29 publications

Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck

Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck

Responses of Human Colorectal Tumor Cells to Treatment with the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody ICR62 Used Alone and in Combination with the EGFR Tyrosine Kinase Inhibitor Gefitinib

The combination of antitumor drugs, exemestane and erlotinib, induced resistance mechanism in H358 and A549 non-small cell lung cancer (NSCLC) cell lines

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