Dual-Agent Molecular Targeting of the Epidermal Growth Factor Receptor (EGFR)

Huang, Shyhmin; Armstrong, Eric A.; Benavente, Sergio; Chinnaiyan, Prakash; Harari, Paul M.

doi:10.1158/0008-5472.can-04-0562

Cited by 358 publications

(232 citation statements)

References 14 publications

Supporting

Mentioning

219

Contrasting

Unclassified

Order By: Relevance

“…It must be underlined that, when examining the different cell lines which were explored in these two latter studies, the supra-additivity of the dual EGFR targeting was not found in all explored cell lines; these cell lines differed markedly between them for the EGFR content. Differences in intrinsic EGFR tumoral expression may modulate the final impact of the dual EGFR targeting and explain the differences between the present conclusions and those reported by the two other groups (Huang et al, 2004;Matar et al, 2004). In the present study, the infra-additive impact on cell survival was sustained by the changes in cleaved PARP, a faithful molecular indicator of apoptotic process, showing that C225-ZD1839 caused less apoptosis than ZD1839 alone.…”

Section: Discussioncontrasting

confidence: 69%

“…Taken together, the above-mentioned arguments provided justification for testing the combination of C225 and ZD1839. A recent study by Huang et al (2004) examined the antitumour effects resulting from this dual combination more marked tumour regressions were observed with the combination of ZD1839 and C225 in mice bearing a human lung cancer xenograft. Another recent study by Matar et al (2004), based on both in vitro and in vivo data, led to similar conclusions.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, when combining data from cell survival and those obtained by examining molecular factors, there are strong concording arguments suggesting that the combination of the two drugs triggers less than additive cytotoxic effects. The studies by Huang et al (2004) and Matar et al (2004) were based on in vitro and in vivo experiments. It must be underlined that, when examining the different cell lines which were explored in these two latter studies, the supra-additivity of the dual EGFR targeting was not found in all explored cell lines; these cell lines differed markedly between them for the EGFR content.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

2005

View full text Add to dashboard Cite

Among the recent advances in the molecular targeted therapy of cancer, the applications focused on epidermal growth factor receptor (EGFR) are currently the most promising and the most advanced at clinical level. In view of the different modes of action of monoclonal antibodies and tyrosine kinase inhibitors (TKI), it is tempting to examine the effect of a combination between these two EGFR targeting approaches. It was the purpose of the present study to test this combination at experimental level by using two epidermoid human cell lines CAL 33 and CAL 39. As C225 (Cetuximab s ) and ZD1839 (Iressa s ) are, respectively, the most clinically advanced drugs in the category of anti-EGFR drugs, the experiments were performed using these two representative compounds. The combination of C225 and ZD1839 was antagonistic whatever the cell line considered. These antagonistic effects were corroborated by molecular changes in apoptosis (PARP) and EGFR signalling (phospho-p42 -44). Drugs alone led to a diminution in EGFR levels, while their combination increased the cellular expression in EGFR. These data suggest that new and tempting treatment strategies on the EGFR target consisting in a double hit with a monoclonal antibody and a TKI must be considered with caution.

show abstract

Section: Discussioncontrasting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

2005

View full text Add to dashboard Cite

show abstract

“…At least three independent groups, (Johns et al, 2003;Huang et al, 2004;Matar et al, 2004;Perera et al, 2005). In further support of this approach we have observed promising clinical activity of the combination of an EGFR TKI and cetuximab, a monoclonal antibody directed at the extracellular domain of the EGFR .…”

Section: Lapatinib-induced Stabilization and Accumulation Of Her2mentioning

confidence: 65%

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

et al. 2008

View full text Add to dashboard Cite

Lapatinib is a human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor (TKI) that has clinical activity in HER2-amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially nonoverlapping mechanisms of action. To dissect these mechanisms, we have studied the effects of lapatinib and trastuzumab on receptor expression and receptor signaling and have identified a new potential mechanism for the enhanced antitumor activity of the combination. Lapatinib, given alone or in combination with trastuzumab to HER2-overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation, prevented receptor ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modeling techniques we have shown that the lapatinib-induced HER2 accumulation at the cell surface also results in the stabilization of inactive HER2 homo-(HER2/HER2) and hetero-(HER2/EGFR and HER2/HER3) dimers. Lapatinibinduced accumulation of HER2 and trastuzumab-mediated downregulation of HER2 was also observed in vivo, where the combination of the two agents triggered complete tumor remissions in all cases after 10 days of treatment. Accumulation of HER2 at the cell surface by lapatinib enhanced immune-mediated trastuzumab-dependent cytotoxicity. We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors.

show abstract

“…Some preclinical studies (Huang et al, 2004;Matar et al, 2004) but not all showed synergistic effect, but solid clinical data are lacking.…”

Section: Combination Of Targeted Therapiesmentioning

confidence: 99%

Current role of antibody therapy in patients with metastatic colorectal cancer

2007

View full text Add to dashboard Cite

Dual-Agent Molecular Targeting of the Epidermal Growth Factor Receptor (EGFR)

Cited by 358 publications

References 14 publications

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

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

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

Current role of antibody therapy in patients with metastatic colorectal cancer

Contact Info

Product

Resources

About