Dual inhibition of EGFR and VEGFR pathways in combination with irradiation: antitumour supra-additive effects on human head and neck cancer xenografts

Bozec, Alexandre; Formento, Patricia; Lassalle, Sandra; Lippens, C; Hofman, Paul; Milano, Gérard

doi:10.1038/sj.bjc.6603791

Cited by 60 publications

(51 citation statements)

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“…Interestingly, the combination of the two drugs produced supra-additive effects on the primary tumour mass with a combination ratio value at 2. We recently made a similar observation when applying on CAL33 cells growing as a classical xenograft the anti-angiogenic multi-target tyrosine kinase inhibitor AZD2171 associated with the anti-EGFR agent gefitinib (Bozec et al, 2007). One of the possible explanations for the presently observed supra-additive anti-tumour activity may lie in an optimal 'vertical blockade' of VEGF pathway not obtained by either agent alone bearing in mind that EGFR targeting leads to inhibition of VEGF tumour secretion (Byers and Heymach, 2007).…”

Section: Discussionmentioning

confidence: 92%

“…In total, this study provides another strong rationale for a combination between irradiation and EGFR pathway targeting plus anti-angiogenic treatment (Bozec et al, 2007). The conclusion drawn from the specific experimental conditions with a head and neck cancer orthotopic xenograft model strengthens the clinical applicability of the presently investigated treatment strategy not only for the management of head and neck cancer but also for other major tumour pathologies such as non-small-cell lung cancer (Maione et al, 2006), colorectal cancer (Arsene et al, 2006) and glioblastoma multiforme (Newton, 2007) in which EGFR targeting and anti-angiogenic treatments are particularly active.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study (Bozec et al, 2007), we investigated the effects of combining anti-angiogenic treatment, EGFR targeting and RT. We evaluated AZD2171, a highly potent, orally active, VEGF signalling inhibitor, gefitinib, an EGFR tyrosine kinase inhibitor, and RT.…”

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confidence: 99%

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Combined effects of bevacizumab with erlotinib and irradiation: a preclinical study on a head and neck cancer orthotopic model

et al. 2008

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Clinical benefit has been demonstrated in patients with head and neck tumours receiving an anti-epidermal growth factor receptor (EGFR) agent in combination with radiotherapy (RT). Recent preclinical and clinical studies suggest beneficial effects from combining anti-angiogenic drugs with RT. To investigate the effect of combining these approaches, we evaluated in vivo the anti-tumour efficacy of the anti-angiogenic compound bevacizumab, a highly specific monoclonal antibody directed against the vascular endothelial growth factor (VEGF), erlotinib, an EGFR tyrosine kinase inhibitor, and irradiation given alone and in combination. Investigations were performed using a VEGF-secreting human head and neck tumour cell line, CAL33, with a high EGFR content, injected as orthotopic xenografts into the mouth floor of nude mice. Three days after tumour cell injection, bevacizumab (5 mg kg À1 , 5 days a week, i.p.), erlotinib (100 mg kg À1 , 5 days a week, orally) and irradiation (6 Gy, 3 days a week) were administered alone and in combination for 10 days. As compared with the control, concomitant administration of drugs produced a marked and significant supra-additive decrease in tumour mass; the addition of irradiation almost completely abolished tumour growth. The drug association markedly reduced the number of metastatic nodes and the triple combination significantly reduced the total number of pathologically positive lymph nodes as compared with controls. The RT-induced proliferation, reflected by Ki67 labelling, was reduced to control level with the triple combination. Radiotherapy induced a strong and very significant increase in tumour angiogenesis, which was no longer observed when combined with erlotinib and bevacizumab. The efficacy of the combination of bevacizumab þ erlotinib and RT may be of clinical importance in the management of head and neck cancer patients.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Combined effects of bevacizumab with erlotinib and irradiation: a preclinical study on a head and neck cancer orthotopic model

et al. 2008

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“…More work could be focused on which critical signaling pathway(s) regulated cell death in tumor cells exposed to irradiation besides the EGFR signaling elucidated by Dittmann et al [22,25]. The potential related signaling include beta-catenin/TCF4 [26], vascular endothelial growth factor (VEGF) signaling [27], and downstreaming p44/42 and Akt signaling. All these signals are still not well-elucidated in cervical tumors treated by radiation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of EGFR nuclear shuttling decreases irradiation resistance in HeLa cells

Wei

Zhu

2017

Folia Histochem Cytobiol.

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Introduction. Cervical cancer is a leading cause of mortality in women worldwide. The resistance to irradiation at the advanced stage is the main reason for the poor prognosis and high mortality. This work aims to elucidate the molecular mechanism underlying the radio-resistance. Material and methods. In this study, we determined the pEGFR-T654 and pDNA-PK-T2609 expression level changes in irradiated HeLa cells treated with T654 peptide, a nuclear localization signal (NLS) inhibitor, to inhibit EGFR nuclear transport. Cell viability, cell cycle and migratory capacity were analyzed. Xenograft animal model was used to evaluate the effect of EGFR nuclear transport inhibition on the tumor growth in vivo. Results. The enhanced translocation of nuclear EGFR in the irradiated HeLa cells correlated with the increasing level of pEGFR-T654 and pDNA-PK-T2609. Inhibition of EGFR nuclear translocation by NLS peptide inhibitor attenuated DNA damage repair in the irradiated HeLa cells, decreased cell viability and promoted cell death through arrest at G0 phase. NLS peptide inhibitor impaired the migratory capacity of irradiated HeLa cells, and negatively affected tumorigenesis in xenograft mice. Conclusions. This work puts forward a potential molecular mechanism of the irradiation resistance in cervical cancer cells, providing a promising direction towards an efficient therapy of cervical cancer.

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“…We, thus, recently investigated the effects of a combination of AZD2171 -a highly potent, orally active, VEGF-signalling inhibitorgefitinib and irradiation (Bozec et al, 2007). The antitumour efficacy of these treatments, administered alone or in combination, was assessed in a human head and neck tumour cell line, CAL33, established as xenografts in nude mice.…”

Section: A Ray Of Hopementioning

confidence: 99%

EGFR-targeting drugs in combination with cytotoxic agents: from bench to bedside, a contrasted reality

Milano

Leyland‐Jones

2008

Br J Cancer

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The clinical experience recently reported with epidermal growth factor receptor (EGFR)-targeting drugs confirms the synergistic interactions observed between these compounds and conventional cytotoxic agents, which were previously established at the preclinical stage. There are, however, examples of major gaps between the bench and the bedside. Particularly demonstrative is the failure of the tyrosine kinase inhibitors (TKIs) (gefitinib and erlotinib) combined with chemotherapy in pretreated nonsmall cell lung cancer patients. These discrepancies can be due to several factors such as the methodology used to evaluate TKI plus cytotoxic agent combinations in preclinical models and the insufficient consideration given to the importance of the drug sequences for the tested combinations. Recent advances in understanding the biologic basis of acquired resistance to these agents have great potential to improve their clinical effectiveness. The purpose of this review is to critically examine the experimental conditions of the preclinical background for anti-EGFR drug -cytotoxic agent combinations and to attempt to explain the gap between clinical observations and preclinical data. The epidermal growth factor receptor (EGFR) is present in many cell types and can be considered as one of the best-characterised ligand-receptor systems (Mendelsohn and Baselga, 2006). Epidermal growth factor receptor is a 170-kDa cell surface glycoprotein containing three well-identified domains: an extracellular ligandbinding domain, a hydrophobic membrane-spanning domain and a cytoplasmic portion containing the tyrosine kinase activity. The hyperactivation of EGFR signalling in tumours occurs via independent or combined mechanisms: overexpression of the receptor itself, autocrine overproduction of ligand with mainly EGF and tumour growth factor (TGFa), and EGFR mutations, notably through the variant III that maintains the EGFR signalling pathway in a state of continuous activation. Binding of a growth factor to its receptor initiates organised and oriented biochemical intracellular events. These include the activation of the receptor, a cascade of phosphorylation with different protein kinases and, at the nuclear level, the activation of transcription factors. The effects of EGFR activation on tumour cells are multiple and convergent, thus favouring uncontrolled cell growth with an increase in cell mobility and cell proliferation, a decrease in apoptotic machinery and stimulation of angiogenesis. In the clinic, EGFR overexpression has been associated with chemoresistance, disease progression and poor survival (Baselga, 2002). Considering the set of therapeutic tools targeting EGFR (Castillo et al, 2004), there are two well-identified categories of drugs, with monoclonal antibodies (mAbs) on one hand and tyrosine kinase inhibitors (TKIs) on the other. Both treatment tools have reached a mature stage of clinical development. Current therapeutic applications with anti-EGFR drugs show encouraging clinical results. This is true mainly for combin...

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Dual inhibition of EGFR and VEGFR pathways in combination with irradiation: antitumour supra-additive effects on human head and neck cancer xenografts

Cited by 60 publications

References 20 publications

Combined effects of bevacizumab with erlotinib and irradiation: a preclinical study on a head and neck cancer orthotopic model

Combined effects of bevacizumab with erlotinib and irradiation: a preclinical study on a head and neck cancer orthotopic model

Inhibition of EGFR nuclear shuttling decreases irradiation resistance in HeLa cells

EGFR-targeting drugs in combination with cytotoxic agents: from bench to bedside, a contrasted reality

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