Epidermal growth factor receptor (EGFR) as a target in cancer therapy: understanding the role of receptor expression and other molecular determinants that could influence the response to anti-EGFR drugs

Ciardiello, Fortunato; Tortora, Giampaolo

doi:10.1016/s0959-8049(03)00235-1

Cited by 225 publications

(156 citation statements)

References 27 publications

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“…Several lines of evidence have shown that EGFR is highly expressed in NSCLC, and some studies have shown that EGFR appears to have a prognostic value in patients with lung cancer [30] . Erlotinib is a small molecule tyrosine kinase inhibitor that targets EGFR at an intracellular site and inhibits EGFR-mediated intracellular signaling by blocking the autophosphorylation of EGFR [21] .…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

et al. 2013

Acta Pharmacol Sin

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Aim: Erlotinib is used to treat non-small-cell lung cancer (NSCLC), which targets epidermal growth factor receptor (EGFR) tyrosine kinase. The aim of this study was to investigate the relationship between erlotinib plasma concentrations and phosphorylated EGFR (pEGFR) levels, as well as the relationship between pEGFR levels and tumor growth inhibition in a human non-small-cell lung cancer xenograft mouse model. Methods: Female BALB/c nude mice were implanted with the human NSCLC cell line SPC-A-1. The animals were given via gavage a single dose of erlotinib (4, 12.5, or 50 mg/kg). Pharmacokinetics of erlotinib was determined using LC-MS/MS. Tumor volume and pEGFR levels in tumor tissues were measured at different time points after erlotinib administration. The levels of pEGFR in tumor tissues was detected using Western blotting and ELISA assays. Results: The pharmacokinetics of erlotinib was described by a two-compartment model with first order extravascular absorption kinetics. There was a time delay of approximately 2 h between erlotinib plasma concentrations and pEGFR degradation. The time course of pEGFR degradation was reasonably fit by the indirect response model with a calculated IC 50 value of 1.80 μg/mL. The relationship between pEGFR levels and tumor volume was characterized by the integrated model with a K bio value of 0.507 cm 3 /week, which described the impact of pEGFR degradation on tumor growth. Conclusion: The pharmacokinetic/pharmacodynamic properties of erlotinib in a human tumor xenograft model were described by the indirect response model and integrated model, which will be helpful in understanding the detailed processes of erlotinib activity and determining an appropriate dosing regimen in clinical studies.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

et al. 2013

Acta Pharmacol Sin

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“…These observations, associated with the occurrence of erbB1 gene amplification in highgrade gliomas, suggest that maintenance of elevated erbB1 levels is required for erbB1 and its ligand to exert their full oncogenic effects. As consequences of enhanced expression of erbB1, tumoral epithelial cells and glioma cells exhibit increased survival, resistance to induced-cell death and deregulated proliferation (Wu et al, 2000;Yarden and Sliwkowski, 2001;Chakravarti et al, 2002;Ciardiello and Tortora, 2003;Kari et al, 2003). Our results show that TGFa may achieve similar effects on normal astrocytes, without the help of enhanced receptors levels.…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

et al. 2006

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Astrocyte death has been implicated in several neuropathological diseases, but the identification of molecules susceptible of promoting astrocyte survival has been elusive. We investigated whether transforming growth factor alpha (TGFa), an erbB1/EGFR ligand, which promotes glioma progression and affects astrocyte metabolism at embryonic and adult stages, regulates astrocyte survival. Primary serum-free astrocyte cultures from postnatal mouse and fetal human cortices were used. Transforming growth factor alpha protected both species of astrocytes from staurosporine-induced apoptosis. In serum-free medium, mouse astrocytes did not survive beyond 2 months while TGFa-treated astrocytes survived up to 12 months. Transforming growth factor alpha also promoted long-term survival of human astrocytes. We additionally extended TGFa proliferative effects to human astrocytes. After 3 days of permanent application, TGFa induced a major downregulation of both erbB1 and erbB2. This downregulation did not impair the functional activation of the receptors, as ascertained by their tyrosine phosphorylation and the continuous stimulation of both ERK/MAPK and PI3K/Akt pathways up to 7 days, the longest time examined. The full cellular effects of TGFa required activation of both transduction pathways. Enhanced proliferation and survival thus define TGFa as a gliatrophin for mammalian astrocytes. These results demonstrate that in normal, non-transformed astrocytes, sustained and functional erbBs activation is achieved without bypassing ligand-induced receptors downregulation.

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“…Perhaps the level of activated, phosphorylated EGFR is more important than the total EGFR level (Ciardiello and Tortora, 2003;Luo et al, 2005). In a small study, with just 23 patients with irinotecan-resistent mCRC, high expression of phosphorylated EGFR was a predictive factor for high RR after to Cx (Personeni et al, 2005).…”

Section: Predicting Efficacy Of CX and Pamentioning

confidence: 99%

Current role of antibody therapy in patients with metastatic colorectal cancer

2007

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Epidermal growth factor receptor (EGFR) as a target in cancer therapy: understanding the role of receptor expression and other molecular determinants that could influence the response to anti-EGFR drugs

Cited by 225 publications

References 27 publications

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

Current role of antibody therapy in patients with metastatic colorectal cancer

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